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Cancer disrupts intratumoral innate-adaptive immune crosstalk, but how the systemic immune landscape evolves during breast cancer progression remains unclear. We profiled circulating immune cells in stage I-III and stage IV triple-negative breast cancer (TNBC) patients and healthy donors (HDs). Metastatic TNBC (mTNBC) patients had reduced T cells, dendritic cells, and differentiated B cells compared to non-metastatic TNBC patients and HDs, partly linked to prior chemotherapy. Vδ1 γδ T cells from mTNBC patients produced more IL17 than those from HDs. Chemotherapy-naïve mTNBC patients showed increased classical monocytes and neutrophils. Transcriptional, proteomic, and functional analyses revealed that neutrophils in mTNBC exhibited enhanced migratory capacity, elevated granule proteins, and higher ROS production. Some immune changes, such as reduced non-switched B cells and heightened neutrophil migration, were evident in earlier TNBC stages. This study comprehensively maps systemic immunity in TNBC, guiding future research on patient stratification and immunomodulation strategies., Competing Interests: Competing interests: N.A.M.B., E.v.D., H.G., E.C., C.K., M.D., L.V., I.N., R.V., M.L., M.N., I.d.R., and O.B. have no conflicts of interest to declare. H.M.O. reports funding to the institute from Roche in order to perform the Triple B study and an advisory board fee from Novartis, Pfizer, Gilead, AstraZeneca, and Daiichi Sankyo outside the submitted work. L.F.A.W. reports funding to the institute from Genmab BV. M.K. reports funding to the institute from BMS, Roche/ Genentech, AZ, and an advisory role/speakers fee for Alderaan, BMS, Domain Therapeutics, Gilead, Roche, MSD, and Daiichi Sankyo, outside the submitted work. K.E.d.V. reports research funding from Roche/Genentech and is a consultant for Macomics, outside the scope of this work., (© 2025. The Author(s).)

Neutrophils are pivotal in orchestrating tumor-induced systemic inflammation and are increasingly recognized for their critical involvement in both the initiation and progression of cancer. A fundamental facet of neutrophil biology is their migratory capacity, which enables them to extravasate and infiltrate tumors in other tissues, where they carry out essential effector functions. Unraveling the intricate mechanisms of neutrophil motility and migration is crucial for comprehending immune responses and inflammatory processes, shedding light on their substantial contribution to cancer progression. Here, we provide a comprehensive protocol to assess direct ex vivo motility and migration of freshly isolated human neutrophils, offering valuable insights into their behavior., Competing Interests: Conflicts of interest N.A.M.B. and C.B. have no conflicts of interest to declare. K.E.d.V. reports research funding from Roche/Genentech and is consultant for Macomics, outside the scope of this work., (Copyright © 2025 Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

Immune checkpoint inhibition (ICI) with chemotherapy is now the standard of care for stage II-III triple-negative breast cancer; however, it is largely unknown for which patients ICI without chemotherapy could be an option and what the benefit of combination ICI could be. The adaptive BELLINI trial explored whether short combination ICI induces immune activation (primary end point, twofold increase in CD8 + T cells or IFNG), providing a rationale for neoadjuvant ICI without chemotherapy. Here, in window-of-opportunity cohorts A (4 weeks of anti-PD-1) and B (4 weeks of anti-PD-1 + anti-CTLA4), we observed immune activation in 53% (8 of 15) and 60% (9 of 15) of patients, respectively. High levels of tumor-infiltrating lymphocytes correlated with response. Single-cell RNA sequencing revealed that higher pretreatment tumor-reactive CD8 + T cells, follicular helper T cells and shorter distances between tumor and CD8 + T cells correlated with response. Higher levels of regulatory T cells after treatment were associated with nonresponse. Based on these data, we opened cohort C for patients with high levels of tumor-infiltrating lymphocytes (≥50%) who received 6 weeks of neoadjuvant anti-PD-1 + anti-CTLA4 followed by surgery (primary end point, pathological complete response). Overall, 53% (8 of 15) of patients had a major pathological response (<10% viable tumor) at resection, with 33% (5 of 15) having a pathological complete response. All cohorts met Simon's two-stage threshold for expansion to stage II. We observed grade ≥3 adverse events for 17% of patients and a high rate (57%) of immune-mediated endocrinopathies. In conclusion, neoadjuvant immunotherapy without chemotherapy demonstrates potential efficacy and warrants further investigation in patients with early triple-negative breast cancer. ClinicalTrials.gov registration: NCT03815890 ., Competing Interests: Competing interests R.M.M. reports research grants from Siemens Healhtineers, Bayer Healthcare, Screenpoint Medical, Beckton & Dickinson, PA Imaging, Lunit and Koning, and is an advisory board member for Screenpoint, Bayer, Siemens and Guerbet, all outside the scope of this work. E. Kalashnikova is an employee of Natera. G.S.S. reports research funding to the institute from Merck, Agendia, AstraZeneca, Roche and Novartis and a consulting role for Novartis, Seattle Genetics and Biovica, outside the submitted work. S.C.L. reports research funding to the institute from Roche/Genentech, AstraZeneca, BMS, Tesaro, Merck, Immunomedics, Eurocept Pharmaceuticals, Agendia and Novartis and a consulting role and travel grant from Daiichi Sankyo, outside this work. C.U.B. has received research grants from Novartis, BMS and NanoString, is a paid advisory board member for BMS, MSD, Roche, Novartis, GlaxoSmithKline, AstraZeneca, Pfizer, Lilly, GenMab and Pierre Fabre and holds ownership interest in Uniti Card, Neon Therapeutics and Forty Seven, all outside this submitted work. K.E.d.V. reports research funding from Roche and is a consultant for Macomics, outside the scope of this work. R.S. reports nonfinancial support from Merck and BMS, research support from Merck, Puma Biotechnology and Roche and personal fees from Roche, BMS and Exact Sciences for advisory boards, all outside the scope of this paper. L.F.A.W. reports funding to the institute from Genmab BV. T.N.S. is an advisor for Allogene Therapeutics, Asher Bio, Merus, Neogene Therapeutics and Scenic Biotech; is a stockholder in Allogene Therapeutics, Asher Bio, Cell Control, Celsius, Merus and Scenic Biotech; and is venture partner at Third Rock Ventures, all outside of the current work. M.K. reports research funding to the institute from BMS, Roche and AstraZeneca/MedImmune and an advisory role/speakers’ fee (all compensated to the institute) for Alderaan, BMS, Domain Therapeutics, Medscape, Roche, MSD and Daiichi Sankyo, outside the submitted work. Natera provided nonfinancial support to this study. The other authors declare no competing interests., (© 2024. The Author(s).)

The TP53 gene is mutated in approximately 30% of all breast cancer cases. Adipocytes and preadipocytes, which constitute a substantial fraction of the stroma of normal mammary tissue and breast tumors, undergo transcriptional, metabolic, and phenotypic reprogramming during breast cancer development and play an important role in tumor progression. We report here that p53 loss in breast cancer cells facilitates the reprogramming of preadipocytes, inducing them to acquire a unique transcriptional and metabolic program that combines impaired adipocytic differentiation with augmented cytokine expression. This, in turn, promotes the establishment of an inflammatory tumor microenvironment, including increased abundance of Ly6C+ and Ly6G+ myeloid cells and elevated expression of the immune checkpoint ligand PD-L1. We also describe a potential gain-of-function effect of common p53 missense mutations on the inflammatory reprogramming of preadipocytes. Altogether, our study implicates p53 deregulation in breast cancer cells as a driver of tumor-supportive adipose tissue reprogramming, expanding the network of non-cell autonomous mechanisms whereby p53 dysfunction may promote cancer. Further elucidation of the interplay between p53 and adipocytes within the tumor microenvironment may suggest effective therapeutic targets for the treatment of breast cancer patients., Competing Interests: Competing interests statement:K.E.d.V. is consultant for Macomics.

Purpose: Patients with postpartum breast cancer diagnosed after cessation of breastfeeding (postweaning, PP-BCPW) have a particularly poor prognosis compared with patients diagnosed during lactation (PP-BCDL), or to pregnant (Pr-BC) and nulliparous (NP-BC) patients, regardless of standard prognostic characteristics. Animal studies point to a role of the involution process in stimulation of tumor growth in the mammary gland. However, in women, the molecular mechanisms that underlie this poor prognosis of patients with PP-BCPW remain vastly underexplored, due to of lack of adequate patient numbers and outcome data., Experimental Design: We explored whether distinct prognostic features, common to all breast cancer molecular subtypes, exist in postpartum tumor tissue. Using detailed breastfeeding data, we delineated the postweaning period in PP-BC as a surrogate for mammary gland involution and performed whole transcriptome sequencing, immunohistochemical, and (multiplex) immunofluorescent analyses on tumor tissue of patients with PP-BCPW, PP-BCDL, Pr-BC, and NP-BC., Results: We found that patients with PP-BCPW having a low expression level of an immunoglobulin gene signature, but high infiltration of plasma B cells, have an increased risk for metastasis and death. Although PP-BCPW tumor tissue was also characterized by an increase in CD8+ cytotoxic T cells and reduced distance among these cell types, these parameters were not associated with differential clinical outcomes among groups., Conclusions: These data point to the importance of plasma B cells in the postweaning mammary tumor microenvironment regarding the poor prognosis of PP-BCPW patients. Future prospective and in-depth research needs to further explore the role of B-cell immunobiology in this specific group of young patients with breast cancer., (©2023 The Authors; Published by the American Association for Cancer Research.)

The clinical successes of immune checkpoint blockade (ICB) in advanced cancer patients have recently spurred the clinical implementation of ICB in the neoadjuvant and perioperative setting. However, how neoadjuvant ICB therapy affects the systemic immune landscape and metastatic spread remains to be established. Tumors promote both local and systemic expansion of regulatory T cells (T regs ), which are key orchestrators of tumor-induced immunosuppression, contributing to immune evasion, tumor progression and metastasis. T regs express inhibitory immune checkpoint molecules and thus may be unintended targets for ICB therapy counteracting its efficacy. Using ICB-refractory models of spontaneous primary and metastatic breast cancer that recapitulate the poor ICB response of breast cancer patients, we observed that combined anti-PD-1 and anti-CTLA-4 therapy inadvertently promotes proliferation and activation of T regs in the tumor, tumor-draining lymph node and circulation. Also in breast cancer patients, T reg levels were elevated upon ICB. Depletion of T regs during neoadjuvant ICB in tumor-bearing mice not only reshaped the intratumoral immune landscape into a state favorable for ICB response but also induced profound and persistent alterations in systemic immunity, characterized by elevated CD8+ T cells and NK cells and durable T cell activation that was maintained after treatment cessation. While depletion of T regs in combination with neoadjuvant ICB did not inhibit primary tumor growth, it prolonged metastasis-related survival driven predominantly by CD8+ T cells. This study demonstrates that neoadjuvant ICB therapy of breast cancer can be empowered by simultaneous targeting of T regs, extending metastasis-related survival, independent of a primary tumor response., Competing Interests: K.E.d.V. reports research funding from Roche and is consultant for Macomics, outside the scope of this work. M.K. reports funding to the institute from BMS, Roche/Genentech, AZ and an advisory role for BMS, Roche, MSD and Daiichi Sankyo, outside the submitted work., (© 2023 The Author(s). Published with license by Taylor & Francis Group, LLC.)

Invasive lobular breast cancer (ILC) is the second most common histological breast cancer subtype, but ILC-specific trials are lacking. Translational research revealed an immune-related ILC subset, and in mouse ILC models, synergy between immune checkpoint blockade and platinum was observed. In the phase II GELATO trial ( NCT03147040 ), patients with metastatic ILC were treated with weekly carboplatin (area under the curve 1.5 mg ml -1 min -1 ) as immune induction for 12 weeks and atezolizumab (PD-L1 blockade; triweekly) from the third week until progression. Four of 23 evaluable patients had a partial response (17%), and 2 had stable disease, resulting in a clinical benefit rate of 26%. From these six patients, four had triple-negative ILC (TN-ILC). We observed higher CD8 + T cell infiltration, immune checkpoint expression and exhausted T cells after treatment. With this GELATO trial, we show that ILC-specific clinical trials are feasible and demonstrate promising antitumor activity of atezolizumab with carboplatin, particularly for TN-ILC, and provide insights for the design of highly needed ILC-specific trials., (© 2023. The Author(s).)

Tumours display an astonishing variation in the spatial distribution, composition and activation state of immune cells, which impacts their progression and response to immunotherapy. Shedding light on the mechanisms that govern the diversity and function of immune cells in the tumour microenvironment will pave the way for the development of more tailored immunomodulatory strategies for the benefit of patients with cancer. Cancer cells, by virtue of their paracrine and juxtacrine communication mechanisms, are key contributors to intertumour heterogeneity in immune contextures. In this Review, we discuss how cancer cell-intrinsic features, including (epi)genetic aberrations, signalling pathway deregulation and altered metabolism, play a key role in orchestrating the composition and functional state of the immune landscape, and influence the therapeutic benefit of immunomodulatory strategies. Moreover, we highlight how targeting cancer cell-intrinsic parameters or their downstream immunoregulatory pathways is a viable strategy to manipulate the tumour immune milieu in favour of antitumour immunity., (© 2023. Springer Nature Limited.)

Cancers represent complex ecosystems comprising tumor cells and a multitude of non-cancerous cells, embedded in an altered extracellular matrix. The tumor microenvironment (TME) includes diverse immune cell types, cancer-associated fibroblasts, endothelial cells, pericytes, and various additional tissue-resident cell types. These host cells were once considered bystanders of tumorigenesis but are now known to play critical roles in the pathogenesis of cancer. The cellular composition and functional state of the TME can differ extensively depending on the organ in which the tumor arises, the intrinsic features of cancer cells, the tumor stage, and patient characteristics. Here, we review the importance of the TME in each stage of cancer progression, from tumor initiation, progression, invasion, and intravasation to metastatic dissemination and outgrowth. Understanding the complex interplay between tumor cell-intrinsic, cell-extrinsic, and systemic mediators of disease progression is critical for the rational development of effective anti-cancer treatments., Competing Interests: Declaration of interests K.E.d.V. reports research funding from Roche/Genentech and is a consultant for Macomics. J.A.J. currently serves on the scientific advisory board of Pionyr Immunotherapeutics and received an honorarium for speaking at a research symposium organized by Bristol Meyers Squibb (last 3 years). J.A.J. is also a member of the Cancer Cell editorial advisory board., (Copyright © 2023 Elsevier Inc. All rights reserved.)

CC chemokine receptor 2 (CCR2), a G protein-coupled receptor, plays a role in many cancer-related processes such as metastasis formation and immunosuppression. Since ∼ 20 % of human cancers contain mutations in G protein-coupled receptors, ten cancer-associated CCR2 mutants obtained from the Genome Data Commons were investigated for their effect on receptor functionality and antagonist binding. Mutations were selected based on either their vicinity to CCR2's orthosteric or allosteric binding sites or their presence in conserved amino acid motifs. One of the mutant receptors, namely S101P 2.63 with a mutation near the orthosteric binding site, did not express on the cell surface. All other studied mutants showed a decrease in or a lack of G protein activation in response to the main endogenous CCR2 ligand CCL2, but no change in potency was observed. Furthermore, INCB3344 and LUF7482 were chosen as representative orthosteric and allosteric antagonists, respectively. No change in potency was observed in a functional assay, but mutations located at F116 3.28 impacted orthosteric antagonist binding significantly, while allosteric antagonist binding was abolished for L134Q 3.46 and D137N 3.49 mutants. As CC chemokine receptor 2 is an attractive drug target in cancer, the negative effect of these mutations on receptor functionality and drugability should be considered in the drug discovery process., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Immune checkpoint blockade (ICB) has heralded a new era in cancer therapy. Research into the mechanisms underlying response to ICB has predominantly focused on T cells; however, effective immune responses require tightly regulated crosstalk between innate and adaptive immune cells. Here, we combine unbiased analysis of blood and tumors from metastatic breast cancer patients treated with ICB with mechanistic studies in mouse models of breast cancer. We observe an increase in systemic and intratumoral eosinophils in patients and mice responding to ICB treatment. Mechanistically, ICB increased IL-5 production by CD4 + T cells, stimulating elevated eosinophil production from the bone marrow, leading to systemic eosinophil expansion. Additional induction of IL-33 by ICB-cisplatin combination or recombinant IL-33 promotes intratumoral eosinophil infiltration and eosinophil-dependent CD8 + T cell activation to enhance ICB response. This work demonstrates the critical role of eosinophils in ICB response and provides proof-of-principle for eosinophil engagement to enhance ICB efficacy., Competing Interests: Declaration of interests O.S.B., H.G., L.S., L.V., O.I.I., E.v.D., N.B., C.K., M.D., K. Kersten, M.B., D.P., C.-S.H., K.V., E.A.M.R., D.K., L.H., K. Kos, I.S.A., P.K., R.B., and D.S.T. have no competing interests to declare. M.C. reports funding to the institute from BMS and Roche/Genentech and an advisory role for BMS, outside the submitted work. W.S.M.E.T. reports receiving grants from MSD during the conduct of the PEMBRO-RT trial. P.B. reports receiving grants and medication delivery from MSD during the conduct of the PEMBRO-RT trial as well as grants and consultancy fees from BMS outside the submitted work. E.E.V. is legally responsible for all contracts with pharmaceutical companies at the NKI and reports research funding from BMS, outside the submitted work. L.F.A.W. reports funding to the institute from Genmab BV. K.E.d.V. reports research funding from Roche/Genentech and is consultant for Macomics, outside the scope of this work. M.K. reports funding to the institute from BMS, Roche/Genentech, AZ, and an advisory role for BMS, Roche, MSD, and Daiichi Sankyo, outside the submitted work., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Immunoediting sculpts immunogenicity and thwarts host anti-tumor responses in tumor cells during tumorigenesis; however, it remains unknown whether metabolic programming of tumor cells can be guided by immunosurveillance. Here, we report that T cell-mediated immunosurveillance in early-stage tumorigenesis instructs c-Myc upregulation and metabolic reprogramming in tumor cells. This previously unexplored tumor-immune interaction is controlled by non-canonical interferon gamma (IFNγ)-STAT3 signaling and supports tumor immune evasion. Our findings uncover that immunoediting instructs deregulated bioenergetic programs in tumor cells to empower them to disarm the T cell-mediated immunosurveillance by imposing metabolic tug-of-war between tumor and infiltrating T cells and forming the suppressive tumor microenvironment., Competing Interests: Declaration of interests P.-C.H. is a member of the scientific advisory board for Elixiron Immunotherapeutics and received research grants from Elixiron Immunotherapeutics. P.-C.H. is also a founder of Pilatus Biosciences., (Copyright © 2022 Elsevier Inc. All rights reserved.)

The limited efficacy of immune checkpoint inhibitor treatment in triple-negative breast cancer (TNBC) patients is attributed to sparse or unresponsive tumor-infiltrating lymphocytes, but the mechanisms that lead to a therapy resistant tumor immune microenvironment are incompletely known. Here we show a strong correlation between MYC expression and loss of immune signatures in human TNBC. In mouse models of TNBC proficient or deficient of breast cancer type 1 susceptibility gene (BRCA1), MYC overexpression dramatically decreases lymphocyte infiltration in tumors, along with immune signature remodelling. MYC-mediated suppression of inflammatory signalling induced by BRCA1/2 inactivation is confirmed in human TNBC cell lines. Moreover, MYC overexpression prevents the recruitment and activation of lymphocytes in both human and mouse TNBC co-culture models. Chromatin-immunoprecipitation-sequencing reveals that MYC, together with its co-repressor MIZ1, directly binds promoters of multiple interferon-signalling genes, resulting in their downregulation. MYC overexpression thus counters tumor growth inhibition by a Stimulator of Interferon Genes (STING) agonist via suppressing induction of interferon signalling. Together, our data reveal that MYC suppresses innate immunity and facilitates tumor immune escape, explaining the poor immunogenicity of MYC-overexpressing TNBCs., (© 2022. The Author(s).)

Background: Ductal carcinoma in situ (DCIS) is treated to prevent subsequent ipsilateral invasive breast cancer (iIBC). However, many DCIS lesions will never become invasive. To prevent overtreatment, we need to distinguish harmless from potentially hazardous DCIS. We investigated whether the immune microenvironment (IME) in DCIS correlates with transition to iIBC., Methods: Patients were derived from a Dutch population-based cohort of 10,090 women with pure DCIS with a median follow-up time of 12 years. Density, composition and proximity to the closest DCIS cell of CD20 + B-cells, CD3 + CD8 + T-cells, CD3 + CD8 - T-cells, CD3 + FOXP3 + regulatory T-cells, CD68 + cells, and CD8 + Ki67 + T-cells was assessed with multiplex immunofluorescence (mIF) with digital whole-slide analysis and compared between primary DCIS lesions of 77 women with subsequent iIBC (cases) and 64 without (controls)., Results: Higher stromal density of analysed immune cell subsets was significantly associated with higher grade, ER negativity, HER-2 positivity, Ki67 ≥ 14%, periductal fibrosis and comedonecrosis (P < 0.05). Density, composition and proximity to the closest DCIS cell of all analysed immune cell subsets did not differ between cases and controls., Conclusion: IME features analysed by mIF in 141 patients from a well-annotated cohort of pure DCIS with long-term follow-up are no predictors of subsequent iIBC, but do correlate with other factors (grade, ER, HER2 status, Ki-67) known to be associated with invasive recurrences., (© 2022. The Author(s).)

Fibroblasts strongly impact tumor progression, but whether they prime the pre-metastatic niche is poorly understood. In this issue of Immunity, Gong and Li et al. identify lung-specific immunosuppressive fibroblasts, which are hijacked by breast cancer cells to facilitate metastasis., Competing Interests: Declaration of interest K.E.d.V reports research funding from Roche and is a consultant for Macomics outside the scope of this work., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Neutrophils are not only crucial immune cells for the neutralization of pathogens during infections, but they are also key players in tissue repair and cancer. Several methods are available to investigate the in vivo role of neutrophils in these conditions, including the depletion of neutrophils with neutralizing antibodies against Ly6G, or the blockade of neutrophil recruitment with CXCR2 inhibitors. A limited number of transgenic mouse models were generated that rely on the disruption of genes important for neutrophil development or on the injection of diphtheria toxin to induce neutrophil ablation. However, these methods have various limitations, including a lack of neutrophil specificity, a lack of long-term efficacy, or a lack of the ability to conditionally deplete neutrophils. Therefore, we generated a transgenic mouse model for the inducible and reversible ablation of neutrophils using the ATTAC (Apoptosis Through Targeted Activation of Caspase 8) approach. With the ATTAC strategy, which relies on the expression of the caspase 8-FKBP fusion protein, apoptosis is induced upon administration of a chemical dimerizer (FK506 analogue) that facilitates the dimerization and activation of caspase 8. In order to achieve specific neutrophil depletion, we cloned the ATTAC construct under the human migration inhibitory factor-related protein 8 (hMRP8) promotor. The newly generated hMRP8-ATTAC mice expressed high levels of the transgene in neutrophils, and, as a consequence, dimerizer injection induced an efficient reduction of neutrophil levels in all the organs analyzed under homeostatic conditions. In situations with extensive pressure on the bone marrow to mobilize neutrophils, for instance in the context of cancer, effective neutrophil depletion in this model requires further optimization. In conclusion, we here describe the generation and characterization of a new transgenic model for conditional neutrophil ablation and highlight the need to improve the ATTAC strategy for the depletion of large numbers of rapidly generated short-lived cells, such as neutrophils.

Neutrophils are the first responders to infection and inflammation and are thus a critical component of innate immune defense. Understanding the behavior of neutrophils as they act within various inflammatory contexts has provided insights into their role in sterile and infectious diseases; however, the field of neutrophils in cancer is comparatively young. Here, we summarize key concepts and current knowledge gaps related to the diverse roles of neutrophils throughout cancer progression. We discuss sources of neutrophil heterogeneity in cancer and provide recommendations on nomenclature for neutrophil states that are distinct in maturation and activation. We address discrepancies in the literature that highlight a need for technical standards that ought to be considered between laboratories. Finally, we review emerging questions in neutrophil biology and innate immunity in cancer. Overall, we emphasize that neutrophils are a more diverse population than previously appreciated and that their role in cancer may present novel unexplored opportunities to treat cancer., (© 2022 Quail et al.)

While regulatory T cells (T regs ) and macrophages have been recognized as key orchestrators of cancer-associated immunosuppression, their cellular crosstalk within tumors has been poorly characterized. Here, using spontaneous models for breast cancer, we demonstrate that tumor-associated macrophages (TAMs) contribute to the intratumoral accumulation of T regs by promoting the conversion of conventional CD4 + T cells (T convs ) into T regs . Mechanistically, two processes were identified that independently contribute to this process. While TAM-derived TGF-β directly promotes the conversion of CD4 + T convs into T regs in vitro , we additionally show that TAMs enhance PD-1 expression on CD4 + T cells. This indirectly contributes to the intratumoral accumulation of T regs , as loss of PD-1 on CD4 + T convs abrogates intratumoral conversion of adoptively transferred CD4 + T convs into T regs . Combined, this study provides insights into the complex immune cell crosstalk between CD4 + T cells and TAMs in the tumor microenvironment of breast cancer, and further highlights that therapeutic exploitation of macrophages may be an attractive immune intervention to limit the accumulation of T regs in breast tumors., Competing Interests: K.E.d.V. reports research funding from Roche/Genentech and is consultant for Macomics. C.R is an employee of Roche and owns intellectual property for the use of CSF1R-inhibitors. M.S. is an employee of Roche., (© 2022 The Author(s). Published with license by Taylor & Francis Group, LLC.)

Breast cancer is accompanied by systemic immunosuppression, which facilitates metastasis formation, but how this shapes organotropism of metastasis is poorly understood. Here, we investigate the impact of mammary tumorigenesis on regulatory T cells (T regs ) in distant organs and how this affects multi-organ metastatic disease. Using a preclinical mouse mammary tumor model that recapitulates human metastatic breast cancer, we observe systemic accumulation of activated, highly immunosuppressive T regs during primary tumor growth. Tumor-educated T regs show tissue-specific transcriptional rewiring in response to mammary tumorigenesis. This has functional consequences for organotropism of metastasis, as T reg depletion reduces metastasis to tumor-draining lymph nodes, but not to lungs. Mechanistically, we find that T regs control natural killer (NK) cell activation in lymph nodes, thereby facilitating lymph node metastasis. In line, an increased T reg /NK cell ratio is observed in sentinel lymph nodes of breast cancer patients compared with healthy controls. This study highlights that immune regulation of metastatic disease is highly organ dependent., Competing Interests: Declaration of interests K.E.d.V. reports research funding from Roche/Genentech and is a consultant for Macomics outside the scope of this work. R.v.d.V. reports research funding from Genmab. T.D.d.G. received research support from Idera Pharmaceuticals; advisory/consultancy fees from LAVA Therapeutics, Parner Therapeutics, and Immunicum; and owns stock from LAVA Therapeutics., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

The gut microbiota strongly impacts the development of sporadic colorectal cancer (CRC), but it is largely unknown how the microbiota affects the pathogenesis of mismatch-repair-deficient CRC in the context of Lynch syndrome. In a mouse model for Lynch syndrome, we found a nearly complete loss of intestinal tumor development when animals were transferred from a conventional "open" animal facility to specific-pathogen-free (SPF) conditions. Using 16S sequencing we detected large changes in microbiota composition between the two facilities. Transcriptomic analyses of tumor-free intestinal tissues showed signs of strong intestinal inflammation in conventional mice. Whole exome sequencing of tumors developing in Msh2-Lynch mice revealed a much lower mutational load in the single SPF tumor than in tumors developing in conventional mice, suggesting reduced epithelial proliferation in SPF mice. Fecal microbiota transplantations with conventional feces altered the immune landscape and gut homeostasis, illustrated by increased gut length and elevated epithelial proliferation and migration. This was associated with drastic changes in microbiota composition, in particular increased relative abundances of different mucus-degrading taxa such as Desulfovibrio and Akkermansia , and increased bacterial-epithelial contact. Strikingly, transplantation of conventional microbiota increased microsatellite instability in untransformed intestinal epithelium of Msh2-Lynch mice, indicating that the composition of the microbiota influences the rate of mutagenesis in MSH2-deficient crypts.

Macrophages are in the spotlight of cancer immunotherapy research because they exert a wide spectrum of protumorigenic functions. In this issue, Pfirschke and colleagues report that macrophage targeting pulls the strings of the tumor microenvironment, ultimately leading to a coordinated antitumorigenic immune reaction in a lung carcinoma mouse model. See related article by Pfirschke et al., p. 40. (4)., (©2021 American Association for Cancer Research.)

Macrophages can promote tumor development. Preclinically, targeting macrophages by colony-stimulating factor 1 (CSF1)/CSF1 receptor (CSF1R) monoclonal antibodies (mAbs) enhances conventional therapeutics in combination treatments. The physiological distribution and tumor uptake of CSF1R mAbs are unknown. Therefore, we radiolabeled a murine CSF1R mAb and preclinically visualized its biodistribution by PET. CSF1R mAb was conjugated to N -succinyl-desferrioxamine ( N -suc-DFO) and subsequently radiolabeled with zirconium-89 ( 89 Zr). Optimal protein antibody dose was first determined in non-tumor-bearing mice to assess physiological distribution. Next, biodistribution of optimal protein dose and 89 Zr-labeled isotype control was compared with PET and ex vivo biodistribution after 24 and 72 h in mammary tumor-bearing mice. Tissue autoradiography and immunohistochemistry determined radioactivity distribution and tissue macrophage presence, respectively. [ 89 Zr]Zr-DFO- N -suc-CSF1R-mAb optimal protein dose was 10 mg/kg, with blood pool levels of 10 ± 2% injected dose per gram tissue (ID/g) and spleen and liver uptake of 17 ± 4 and 11 ± 4%ID/g at 72 h. In contrast, 0.4 mg/kg of [ 89 Zr]Zr-DFO- N -suc-CSF1R mAb was eliminated from circulation within 24 h; spleen and liver uptake was 126 ± 44% and 34 ± 7%ID/g, respectively. Tumor-bearing mice showed higher uptake of [ 89 Zr]Zr-DFO- N -suc-CSF1R-mAb in the liver, lymphoid tissues, duodenum, and ileum, but not in the tumor than did 89 Zr-labeled control at 72 h. Immunohistochemistry and autoradiography showed that 89 Zr was localized to macrophages within lymphoid tissues. Following [ 89 Zr]Zr-DFO- N -suc-CSF1R-mAb administration, tumor macrophages were almost absent, whereas isotype-group tumors contained over 500 cells/mm 2 . We hypothesize that intratumoral macrophage depletion by [ 89 Zr]Zr-DFO- N -suc-CSF1R-mAb precluded tumor uptake higher than 89 Zr-labeled control. Translation of molecular imaging of macrophage-targeting therapeutics to humans may support macrophage-directed therapeutic development., Competing Interests: EV reports institutional financial support for her advisory role from Daiichi Sankyo, Merck, NSABP, Pfizer, Sanofi, and Synthon and institutional financial support for clinical trials or contracted research from Amgen, AstraZeneca, Bayer, Chugai Pharma, CytomX Therapeutics, G1 Therapeutics, Genentech, Nordic Nanovector, Radius Health, Roche, Synthon, and Servier. CS reports receiving unrestricted research grants from Novartis, Roche, Genentech, Pfizer, SNS Oncology, and G1 Therapeutics that were made available to UMCG. KdV reports receiving research grants from Roche and is a consultant for Third Rock Ventures. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Waaijer, Suurs, Hau, Vrijland, de Visser, de Groot, de Vries, Lub-de Hooge and Schröder.)

The chemokine system, comprising 48 chemokines and 23 receptors, is critically involved in several hallmarks of cancer. Yet, despite extensive efforts from the pharmaceutical sector, only two drugs aimed at this system are currently approved for clinical use against cancer. To date, numerous pharmacological approaches have been developed to successfully intervene at different stages of chemokine function: (i) chemokine availability; (ii) chemokine-glycosaminoglycan binding; and (iii) chemokine receptor binding. Many of these strategies have been tested in preclinical cancer models, and some have advanced to clinical trials as potential anticancer therapies. Here we will review the strategies and growing pharmacological toolbox for manipulating the chemokine system in cancer, and address novel methods poised for future (pre)clinical testing., Competing Interests: Declaration of interests K.E.d.V. reports research funding from Roche/Genentech and is consultant for Third Rock Ventures, outside the scope of this work., (Copyright © 2021. Published by Elsevier Ltd.)

Neutrophils are multifaceted innate immune cells that play a significant role in the progression of cancer by exerting both pro- and anti-tumorigenic functions. The crosstalk between cancer cells and neutrophils is complex and emerging evidence is pointing at cancer cell-intrinsic programs regulating neutrophil abundance, phenotype and function. Cancer cell-derived soluble mediators are key players in modulating the interaction with neutrophils. Here, we review how intrinsic features of cancer cells, including cancer cell genetics, epigenetics, signaling, and metabolism, manipulate neutrophil behavior and how to target these processes to impact cancer progression. A molecular understanding of cancer cell-intrinsic properties that shape the crosstalk with neutrophils will provide novel therapeutic strategies for personalized immunomodulation in cancer patients., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The glucocorticoid receptor (GR) regulates gene expression, governing aspects of homeostasis, but is also involved in cancer. Pharmacological GR activation is frequently used to alleviate therapy-related side-effects. While prior studies have shown GR activation might also have anti-proliferative action on tumours, the underpinnings of glucocorticoid action and its direct effectors in non-lymphoid solid cancers remain elusive. Here, we study the mechanisms of glucocorticoid response, focusing on lung cancer. We show that GR activation induces reversible cancer cell dormancy characterised by anticancer drug tolerance, and activation of growth factor survival signalling accompanied by vulnerability to inhibitors. GR-induced dormancy is dependent on a single GR-target gene, CDKN1C, regulated through chromatin looping of a GR-occupied upstream distal enhancer in a SWI/SNF-dependent fashion. These insights illustrate the importance of GR signalling in non-lymphoid solid cancer biology, particularly in lung cancer, and warrant caution for use of glucocorticoids in treatment of anticancer therapy related side-effects., (© 2021. The Author(s).)

Neutrophils can facilitate the metastatic spread of cancer; however, how neutrophils are activated at metastatic sites remains poorly understood. In this issue, Xiao et al. demonstrate that the protease cathepsin C, secreted by breast cancer cells, triggers neutrophils to form neutrophil extracellular traps in the metastatic niche, thereby promoting lung metastasis., Competing Interests: Declaration of Interests K.E.d.V. reports research funding from Roche and is consultant for Third Rock Ventures, outside the scope of this work., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Sarcomas are rare mesenchymal tumors with a broad histological spectrum, but they can be divided into two groups based on molecular pathology: sarcomas with simple or complex genomics. Tumors with complex genomics can have aneuploidy and copy number gains and losses, which hampers the detection of early, initiating events in tumorigenesis. Often, no benign precursors are known, which is why good models are essential. The mesenchymal stem cell (MSC) is the presumed cell of origin of sarcoma. In this study, MSCs of murine and canine origin are used as a model to identify driver events for sarcomas with complex genomic alterations as they transform spontaneously after long-term culture. All transformed murine but not canine MSCs formed sarcomas after subcutaneous injection in mice. Using whole genome sequencing, spontaneously transformed murine and canine MSCs displayed a complex karyotype with aneuploidy, point mutations, structural variants, inter-chromosomal translocations, and copy number gains and losses. Cross-species analysis revealed that point mutations in Tp53/Trp53 are common in transformed murine and canine MSCs. Murine MSCs with a cre-recombinase induced deletion of exon 2-10 of Trp53 transformed earlier compared to wild-type murine MSCs, confirming the contribution of loss of p53 to spontaneous transformation. Our comparative approach using transformed murine and canine MSCs points to a crucial role for p53 loss in the formation of sarcomas with complex genomics.

The microenvironment of breast cancer hosts a dynamic cross talk between diverse players of the immune system. While cytotoxic immune cells are equipped to control tumor growth and metastasis, tumor-corrupted immunosuppressive immune cells strive to impair effective immunity and promote tumor progression. Of these, regulatory T cells (T regs ), the gatekeepers of immune homeostasis, emerge as multifaceted players involved in breast cancer. Intriguingly, clinical observations suggest that blood and intratumoral T regs can have strong prognostic value, dictated by breast cancer subtype. Accordingly, emerging preclinical evidence shows that T regs occupy a central role in breast cancer initiation and progression and provide critical support to metastasis formation. Here, T regs are not only important for immune escape but also promote tumor progression independent of their immune regulatory capacity. Combining insights into T reg biology with advances made across the rapidly growing field of immuno-oncology is expected to set the stage for the design of more effective immunotherapy strategies., Competing Interests: Disclosure Statement K.E.d.V. reports research funding from Roche and is a consultant for Third Rock Ventures, both of which are outside the scope of this work. K.K. reports no competing interests.

Metastatic disease is responsible for approximately 90% of cancer deaths. For successful dissemination and metastasis, cancer cells must evade detection and destruction by the immune system. This process is enabled by factors secreted by the primary tumour that shape both the intratumoural microenvironment and the systemic immune landscape. Here, we review the evidence of aberrant immune cell crosstalk in metastasis formation and the role that primary tumours play in hijacking these interactions in order to enhance their metastatic potential. Moreover, we highlight the intriguing parallels between the inflammatory pathways underlying inflammatory disorders and cancer progression.

Effective treatment of invasive lobular carcinoma (ILC) of the breast is hampered by late detection, invasive growth, distant metastasis, and poor response to chemotherapy. Phosphoinositide 3-kinase (PI3K) signaling, one of the major druggable oncogenic signaling networks, is frequently activated in ILC. We investigated treatment response and resistance to AZD8055, an inhibitor of mammalian target of rapamycin (mTOR), in the K14-cre;Cdh1 Flox/Flox ;Trp53 Flox/Flox (KEP) mouse model of metastatic ILC. Inhibition of mTOR signaling blocked the growth of primary KEP tumors as well as the progression of metastatic disease. However, primary tumors and distant metastases eventually acquired resistance after long-term AZD8055 treatment, despite continued effective suppression of mTOR signaling in cancer cells. Interestingly, therapeutic responses were associated with increased expression of genes related to antigen presentation. Consistent with this observation, increased numbers of tumor-infiltrating major histocompatibility complex class II-positive (MHCII+) immune cells were observed in treatment-responsive KEP tumors. Acquisition of treatment resistance was associated with loss of MHCII+ cells and reduced expression of genes related to the adaptive immune system. The therapeutic efficacy of mTOR inhibition was reduced in Rag1 -/- mice lacking mature T and B lymphocytes, compared to immunocompetent mice. Furthermore, therapy responsiveness could be partially rescued by transplanting AZD8055-resistant KEP tumors into treatment-naïve immunocompetent hosts. Collectively, these data indicate that the PI3K signaling pathway is an attractive therapeutic target in invasive lobular carcinoma, and that part of the therapeutic effect of mTOR inhibition is mediated by the adaptive immune system., (© 2020 The Author(s). Published with license by Taylor & Francis Group, LLC.)

The progression of cancer is strongly influenced by the crosstalk between cancer cells and immune cells. Immune cells can have both pro- and anti-tumor functions depending on the signals present in the environment. A significant proportion of the immune compartment of most solid tumors consists of tumor-associated macrophages. Although their abundance has been associated with poor prognosis in many solid tumor types, the molecular mechanisms by which cancer cells influence macrophage phenotype and function are largely unknown. In this chapter, we provide a detailed description of in vitro assays to study the impact of cancer cells on macrophages. We provide protocols to obtain macrophages from murine bone marrow and human peripheral blood, and to expose these macrophages to cancer cell-derived secreted molecules using conditioned medium from cancer cells. We describe several assays to assess cancer cell-induced polarization of macrophages. This experimental set-up can be utilized to gain molecular insights into how cancer cells influence macrophages., (© 2020 Elsevier Inc. All rights reserved.)

Regulatory T cells (Tregs) play a major role in establishing an immunosuppressive tumor microenvironment. In order to fully uncover their role and molecular regulation in tumor-bearing hosts, it is critical to combine phenotypical characterization with functional analyses. A standard method to determine the suppressive potential of Tregs is with an in vitro suppression assay, in which the impact of freshly isolated Tregs on T cell proliferation is assessed. The assay requires the isolation of substantial numbers of Tregs from tissues and tumors, which can be challenging due to low yield or cell damage during sample preparation. In this chapter, we discuss a flexible suppression assay which can be used to assess the suppressive potential of low numbers of murine Tregs, directly isolated from tumors. We describe methods for tissue preparation, flow cytometry-based sorting of Tregs and optimal conditions to perform a suppression assay, to obtain reliable and reproducible results., (© 2020 Elsevier Inc. All rights reserved.)

Tumor-associated macrophages (TAMs) are frequently the most abundant immune cells in cancers and are associated with poor survival. Here, we generated TAM molecular signatures from K14cre;Cdh1 flox/flox ;Trp53 flox/flox (KEP) and MMTV-NeuT (NeuT) transgenic mice that resemble human invasive lobular carcinoma (ILC) and HER2 + tumors, respectively. Determination of TAM-specific signatures requires comparison with healthy mammary tissue macrophages to avoid overestimation of gene expression differences. TAMs from the two models feature a distinct transcriptomic profile, suggesting that the cancer subtype dictates their phenotype. The KEP-derived signature reliably correlates with poor overall survival in ILC but not in triple-negative breast cancer patients, indicating that translation of murine TAM signatures to patients is cancer subtype dependent. Collectively, we show that a transgenic mouse tumor model can yield a TAM signature relevant for human breast cancer outcome prognosis and provide a generalizable strategy for determining and applying immune cell signatures provided the murine model reflects the human disease., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Cancer-associated systemic inflammation is strongly linked to poor disease outcome in patients with cancer 1,2 . For most human epithelial tumour types, high systemic neutrophil-to-lymphocyte ratios are associated with poor overall survival 3 , and experimental studies have demonstrated a causal relationship between neutrophils and metastasis 4,5 . However, the cancer-cell-intrinsic mechanisms that dictate the substantial heterogeneity in systemic neutrophilic inflammation between tumour-bearing hosts are largely unresolved. Here, using a panel of 16 distinct genetically engineered mouse models for breast cancer, we uncover a role for cancer-cell-intrinsic p53 as a key regulator of pro-metastatic neutrophils. Mechanistically, loss of p53 in cancer cells induced the secretion of WNT ligands that stimulate tumour-associated macrophages to produce IL-1β, thus driving systemic inflammation. Pharmacological and genetic blockade of WNT secretion in p53-null cancer cells reverses macrophage production of IL-1β and subsequent neutrophilic inflammation, resulting in reduced metastasis formation. Collectively, we demonstrate a mechanistic link between the loss of p53 in cancer cells, secretion of WNT ligands and systemic neutrophilia that potentiates metastatic progression. These insights illustrate the importance of the genetic makeup of breast tumours in dictating pro-metastatic systemic inflammation, and set the stage for personalized immune intervention strategies for patients with cancer.

Understanding how tumors escape from immune attack may offer novel therapeutic opportunities. Veglia et al. (2019) demonstrate in Nature that fatty acid transport protein 2 (FATP2) endows neutrophils with immunosuppressive capabilities that promote cancer growth. This receptor can be targeted to unleash anti-tumor immunity and to potentiate immune checkpoint blockade., (Copyright © 2019 Elsevier Inc. All rights reserved.)

The efficacy of programmed cell death protein 1 (PD-1) blockade in metastatic triple-negative breast cancer (TNBC) is low 1-5 , highlighting a need for strategies that render the tumor microenvironment more sensitive to PD-1 blockade. Preclinical research has suggested immunomodulatory properties for chemotherapy and irradiation 6-13 . In the first stage of this adaptive, non-comparative phase 2 trial, 67 patients with metastatic TNBC were randomized to nivolumab (1) without induction or with 2-week low-dose induction, or with (2) irradiation (3 × 8 Gy), (3) cyclophosphamide, (4) cisplatin or (5) doxorubicin, all followed by nivolumab. In the overall cohort, the objective response rate (ORR; iRECIST 14 ) was 20%. The majority of responses were observed in the cisplatin (ORR 23%) and doxorubicin (ORR 35%) cohorts. After doxorubicin and cisplatin induction, we detected an upregulation of immune-related genes involved in PD-1-PD-L1 (programmed death ligand 1) and T cell cytotoxicity pathways. This was further supported by enrichment among upregulated genes related to inflammation, JAK-STAT and TNF-α signaling after doxorubicin. Together, the clinical and translational data of this study indicate that short-term doxorubicin and cisplatin may induce a more favorable tumor microenvironment and increase the likelihood of response to PD-1 blockade in TNBC. These data warrant confirmation in TNBC and exploration of induction treatments prior to PD-1 blockade in other cancer types.

Recent studies have revealed a role for macrophages and neutrophils in limiting chemotherapy efficacy; however, the mechanisms underlying the therapeutic benefit of myeloid-targeting agents in combination with chemotherapy are incompletely understood. Here, we show that targeting tumour-associated macrophages by colony-stimulating factor-1 receptor (CSF-1R) blockade in the K14cre;Cdh1 F/F ;Trp53 F/F transgenic mouse model for breast cancer stimulates intratumoural type I interferon (IFN) signalling, which enhances the anticancer efficacy of platinum-based chemotherapeutics. Notably, anti-CSF-1R treatment also increased intratumoural expression of type I IFN-stimulated genes in patients with cancer, confirming that CSF-1R blockade is a powerful strategy to trigger an intratumoural type I IFN response. By inducing an inflamed, type I IFN-enriched tumour microenvironment and by further targeting immunosuppressive neutrophils during cisplatin therapy, antitumour immunity was activated in this poorly immunogenic breast cancer mouse model. These data illustrate the importance of breaching multiple layers of immunosuppression during cytotoxic therapy to successfully engage antitumour immunity in breast cancer.

Metastatic disease is the leading cause of death in cancer patients. Metastasis formation involves a cascade of events for which the underlying mechanisms are still poorly understood. During the metastatic cascade, cancer cells tightly interact with the immune system and they influence each other, both in the tumor microenvironment and systemically. The crosstalk between cancer and immune cells adds another layer of complexity to our understanding of metastasis formation, but at the same time opens new therapeutic opportunities for cancer patients. The intensifying development of immunotherapeutic strategies calls for a better understanding of immune regulation of metastasis in order to maximize the therapeutic benefit for patients with metastatic disease. In this Review and accompanying poster, we describe the main mechanisms of immune regulation of metastasis that have been reported to date, and present promising immunotherapeutic options that are currently available, or may become so in the near future, to tackle metastasis., (© 2018. Published by The Company of Biologists Ltd.)

To better understand the expression pattern of programmed death-ligand 1 (PD-L1) expression in different breast cancer types, we characterized PD-L1 expression in tumor and tumor-infiltrating immune cells, in relation to mutation rate, BRCA1 -like status and survival. We analyzed 410 primary treatment-naive breast tumors comprising 162 estrogen receptor-positive (ER+) and HER2-, 101 HER2+ and 147 triple-negative (TN) cancers. Pathologists quantified tumor-infiltrating lymphocytes (TILs) and PD-L1 expression in tumor cells and TILs using whole slides and tissue microarray. Mutation rate was assessed by DNA sequencing, BRCA1 -like status using multiplex ligation-dependent probe amplification, and immune landscape by multiplex image analyses of CD4, CD68, CD8, FOXP3, cytokeratin, and PD-L1. Half of PD-L1 scores evaluated by tissue microarray were false negatives compared to whole slide evaluations. We observed at least 1% of PD-L1-positive (PD-L1+) cells in 53.1% of ER+HER2-, 73.3% of HER2+, and 84.4% of TN tumors. PD-L1 expression was higher in ductal compared to lobular carcinomas, also within ER+HER2- tumors (p = 0.04). High PD-L1+ TILs score (> 50%) was independently associated with better outcome in TN tumors (HR = 0.27; 95%CI = 0.10-0.69). Within TN tumors, PD-L1 and TIL scores showed a modest but significant positive association with the number of silent mutations, but no association with BRCA1 -like status. Multiplex image analyses indicated that PD-L1 is expressed on multiple immune cells (CD68+ macrophages, CD4+, FOXP3+, and CD8+ T cells) in the breast tumor microenvironment, independent of the PD-L1 status of the tumor cells. We found no evidence that levels of PD-L1+ TILs in TN breast cancer are driven by high mutation rate or BRCA1 -like status.

Owing to their tremendous diversity and plasticity, immune cells exert multifaceted functions in tumor-bearing hosts, ranging from anti-tumor to pro-tumor activities. Tumor immune landscapes differ greatly between and within cancer types. Emerging evidence suggests that genetic aberrations in cancer cells dictate the immune contexture of tumors. Here, we review the current understanding of the mechanisms whereby common drivers of tumorigenesis modulate the tumor immune milieu. We discuss these findings in the context of clinical observations and examine how cancer-cell-intrinsic properties can be exploited to maximize the benefit of immunomodulatory therapies. Understanding the relationship between cancer cell-intrinsic genetic events and the immune response may enable personalized immune intervention strategies for cancer patients., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Increasing evidence from epidemiological and pathological studies suggests a role of the immune system in the initiation and progression of multiple cancers, including prostate cancer. Reports on the contribution of the adaptive immune system are contradictive, since both suppression and acceleration of disease development have been reported. This study addresses the functional role of lymphocytes in prostate cancer development using a genetically engineered mouse model (GEMM) of human c-Myc driven prostate cancer (Hi-Myc mice) combined with B and T cell deficiency (RAG1 -/- mice). From a pre-cancerous stage on, Hi-Myc mice showed higher accumulation of immune cells in their prostates then wild-type mice, of which macrophages were the most abundant. The onset of invasive adenocarcinoma was delayed in Hi-MycRAG1 -/- compared to Hi-Myc mice and associated with decreased infiltration of leukocytes into the prostate. In addition, lower levels of the cytokines CXCL2, CCL5 and TGF-β1 were detected in Hi-MycRAG1 -/- compared to Hi-Myc mouse prostates. These results from a GEMM of prostate cancer provide new insights into the promoting role of the adaptive immune system in prostate cancer development. Our findings indicate that the endogenous adaptive immune system does not protect against de novo prostate carcinogenesis in Hi-Myc transgenic mice, but rather accelerates the formation of invasive adenocarcinomas. This may have implications for the development of novel treatment strategies., Competing Interests: CONFLICTS OF INTEREST The authors declare no potential conflicts of interest.