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Profiling spatial distributions of lipids, metabolites, and proteins in tumors can reveal unique cellular microenvironments and provide molecular evidence for cancer cell dysfunction and proliferation. Mass spectrometry imaging (MSI) is a label-free technique that can be used to map biomolecules in tumors in situ. Here, we discuss current progress in applying MSI to uncover molecular heterogeneity in tumors. First, the analytical strategies to profile small molecules and proteins are outlined, and current methods for multimodal imaging to maximize biological information are highlighted. Second, we present and summarize biological insights obtained by MSI of tumor tissue. Finally, we discuss important considerations for designing MSI experiments and several current analytical challenges., 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 © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

The broad effectiveness of T cell-based therapy for treating solid tumour cancers remains limited. This is partly due to the growing appreciation that immune cells must inhabit and traverse a metabolically demanding tumour environment. Accordingly, recent efforts have centred on using genome-editing technologies to augment T cell-mediated cytotoxicity by manipulating specific metabolic genes. However, solid tumours exhibit numerous characteristics restricting immune cell-mediated cytotoxicity, implying a need for metabolic engineering at the pathway level rather than single gene targets. This emerging concept has yet to be put into clinical practice as many questions concerning the complex interplay between metabolic networks and T cell function remain unsolved. This Perspective will highlight key foundational studies that examine the relevant metabolic pathways required for effective T cell cytotoxicity and persistence in the human tumour microenvironment, feasible strategies for metabolic engineering to increase the efficiency of chimeric antigen receptor T cell-based approaches, and the challenges lying ahead for clinical implementation., (© 2024. Springer Nature Limited.)

From 19 to 21 November 2022, BioCanRx held its first post-pandemic in-person Summit for Cancer Immunotherapy in Montreal, Canada. The meeting was well attended by patients, trainees, researchers, clinicians, and industry professionals, who came together to discuss the current state and future of biotherapeutics for cancer in Canada and beyond. Three plenaries, three keynote speakers, a lively debate, and panel discussions, together with poster sessions and a social event, made the event memorable and productive. The current state of cellular therapies, cellular engineering, clinical trials, and the role of the cancer microbiome were discussed in plenary session, and the patient voice was welcomed and present throughout the meeting, in large part due to the Learning Institute, a BioCanRx initiative to include patient partners in research. In this meeting review, we highlight the platform presentations, keynote speakers, debate combatants, panellists, and the patient perspective on the annual meeting., Competing Interests: The authors declare there are no competing interests.

Our understanding of tumor-infiltrating lymphocytes (TILs) is rapidly expanding beyond T cell-centric perspectives to include B cells and plasma cells, collectively referred to as TIL-Bs. In many cancers, TIL-Bs carry strong prognostic significance and are emerging as key predictors of response to immune checkpoint inhibitors. TIL-Bs can perform multiple functions, including antigen presentation and antibody production, which allow them to focus immune responses on cognate antigen to support both T cell responses and innate mechanisms involving complement, macrophages, and natural killer cells. In the stroma of the most immunologically "hot" tumors, TIL-Bs are prominent components of tertiary lymphoid structures, which resemble lymph nodes structurally and functionally. Additionally, TIL-Bs participate in a variety of other lympho-myeloid aggregates and engage in dynamic interactions with the tumor stroma. Here, we summarize our current understanding of TIL-Bs in human cancer, highlighting the compelling therapeutic opportunities offered by their unique tumor recognition and effector mechanisms., Competing Interests: Declaration of interests The authors declare no competing interests., (Crown Copyright © 2023. Published by Elsevier Inc. All rights reserved.)

One method of immune evasion that cancer cells employ is the secretion of immune regulatory metabolites into the tumor microenvironment (TME). These metabolites can promote immunosuppressive cell subsets, while inhibiting key tumor-killing subsets, such as T cells. Thus, the identification of these metabolites may help develop methods for improving cell-based therapy. However, after identifying a potential immune regulatory metabolite, it is crucial to assess the impacts of the metabolite on T cell immunobiology. In this chapter, we describe an in vitro method of testing and analyzing the influence of a specific metabolite on T cell proliferation and function., (© 2023. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose of Review: To discuss the historical development of intermittent fasting, its potential underlying mechanisms, and the state of clinical trials, and to reflect on considerations for practice and future recommendations., Recent Findings: Preclinical studies consistently show the robust disease-modifying efficacy of intermittent fasting in various metabolic diseases which may hold implications for cancer prevention and survivorship. Twenty-one clinical trials have or are being conducted on fasting in cancer, utilizing various fasting regimens across different tumor types as a stand-alone intervention or in adjunct to anticancer treatment, with heterogenous outcome variables. Though there are no known, reproducible diets, to cure or prevent cancer recurrence, preliminary research on the underlying mechanisms, tolerance, and safety of intermittent fasting in cancer warrants further investigation. The inherent flexibility of intermittent fasting to accommodate all types of diets is of necessity in oncology., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Although immunotherapy research to date has focused largely on T cells, there is mounting evidence that tumour-infiltrating B cells and plasma cells (collectively referred to as tumour-infiltrating B lymphocytes (TIL-Bs)) have a crucial, synergistic role in tumour control. In many cancers, TIL-Bs have demonstrated strong predictive and prognostic significance in the context of both standard treatments and immune checkpoint blockade, offering the prospect of new therapeutic opportunities that leverage their unique immunological properties. Drawing insights from autoimmunity, we review the molecular phenotypes, architectural contexts, antigen specificities, effector mechanisms and regulatory pathways relevant to TIL-Bs in human cancer. Although the field is young, the emerging picture is that TIL-Bs promote antitumour immunity through their unique mode of antigen presentation to T cells; their role in assembling and perpetuating immunologically 'hot' tumour microenvironments involving T cells, myeloid cells and natural killer cells; and their potential to combat immune editing and tumour heterogeneity through the easing of self-tolerance mechanisms. We end by discussing the most promising approaches to enhance TIL-B responses in concert with other immune cell subsets to extend the reach, potency and durability of cancer immunotherapy., (© 2022. Springer Nature Limited.)

Background: Over time, researchers' demand for increased quality and quantity of biospecimens has risen. However, quality is multifaceted, ranging from simple to complex, and comes at a cost. Therefore, to be sustainable and ensure optimal utilization of their resources (supply), biobanks must consider the trends in biospecimen use to predict the needs for future biospecimen quality (demand). Methods: An unbiased selection process was used to identify research articles from across the spectrum of cancer research from the PubMed database. A set of 225 articles utilizing human biospecimens were randomly selected for review (75 articles from each of three time intervals; 2000, 2010, 2020). Criteria for determining the source and complexity of quality of biospecimens were developed and overall concordance between two independent observers abstracting the data was then confirmed ( k  = 0.87) to validate the criteria. Results: We observed increased use of dual biospecimen formats (20%-36% of articles, p  = 0.03), matched samples (16%-37% of articles, p  = 0.0033), and biospecimens with associated outcomes data (20%-49%, p  = 0.0002). In addition, the use of two or more cohorts increased over time ( p  = 0.03). The mechanism through which biospecimens were obtained also changed over time with an increase in the diversity of collection pathways used ( p  = 0.006). Conclusions: The complexity of biospecimens being used in cancer research and the diversity of collection pathways through which these are obtained has changed significantly. This observation is important for biobanks given that the cost to support the supply of biospecimens with complex extrinsic as opposed to simple intrinsic quality characteristics is greater. For biobanks to manage sustainability, optimize utilization, and meet changing research demand, they may need to adjust their operational models to better support the supply of these types of biospecimens.

Tumor-infiltrating B cells and plasma cells have emerged as critical players in anti-tumor immunity. A recent report in Nature shows that IgA antibodies produced by these cells can enter tumor cells by transcytosis, impede oncogenic signals, and facilitate T cell-mediated cytotoxicity. These findings reveal a promising new mechanism to exploit for immunotherapy., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Cancer immunotherapy is rapidly developing, with numerous therapies approved over the past decade and more therapies expected to gain approval in the future. However, immunotherapy of solid tumors has been less successful because immunosuppressive barriers limit immune cell trafficking and function against cancer cells. Interactions between suppressive immune cells, cytokines, and inhibitory factors are central to cancer immunotherapy approaches. In this review, we discuss recent advances in utilizing microfluidic platforms for understanding cancer-suppressive immune system interactions. Dendritic cell (DC)-mediated tumor models, infiltrated lymphocyte-mediated tumor models [e.g., natural killer (NK) cells, T cells, chimeric antigen receptor (CAR) T cells, and macrophages], monocyte-mediated tumor models, and immune checkpoint blockade (ICB) tumor models are among the various bioengineered immune cell-cancer cell interactions that we reviewed herein., (Copyright © 2020. Published by Elsevier Ltd.)

Objective: We recently showed that tumors with an immunologically 'cold' phenotype are enriched for expression of stemness-associated genes and PVR/CD155, the ligand of the immunosuppressive molecule TIGIT. To explore the therapeutic implications of this finding, we investigated the relationship between PVR/CD155 expression, tumor-infiltrating lymphocytes (TIL), and prognosis in high-grade serous ovarian cancer (HGSC) and other cancers., Methods: Expression of CD155, TIGIT, PD-1, PD-L1, and other immune markers in HGSC was assessed by high-dimensional flow cytometry, multi-color histological imaging, and/or gene expression profiling. The prognostic significance of PVR/CD155 and CD274/PD-L1 expression was assessed bioinformatically in HGSC and 32 other cancers in The Cancer Genome Atlas., Results: T cells from HGSC frequently co-expressed TIGIT and PD-1, and the ratio of TIGIT to PD-1 expression increased markedly after in vitro expansion with a clinically relevant protocol. CD155 was commonly expressed on malignant epithelium in HGSC and showed a negative or non-significant association with TIL. In contrast, PD-L1 was predominantly expressed by tumor-associated macrophages and positively associated with TIL. These contrasts between CD155 and PD-L1 were seen across HGSC patients, across metastatic sites within individual patients, and even within individual tumor deposits. PVR/CD155 and CD274/PD-L1 exhibited divergent prognostic associations across diverse cancer types in TCGA, including HGSC., Conclusions: CD155 and PD-L1 exhibit contrasting expression patterns, TIL associations and prognostic significance, suggesting they represent non-redundant immunosuppressive mechanisms. The CD155/TIGIT pathway represents a compelling immunotherapeutic target for HGSC and for immunologically cold tumors in general., Competing Interests: Declaration of competing interest No potential conflicts of interest to disclose., (Crown Copyright © 2020. Published by Elsevier Inc. All rights reserved.)

Radiation therapy (RT) is one of the most commonly prescribed cancer treatments. New tools that can accurately monitor and evaluate individual patient responses would be a major advantage and lend to the implementation of personalized treatment plans. In this study, Raman spectroscopy (RS) was applied to examine radiation-induced cellular responses in H460, MCF7, and LNCaP cancer cell lines across different dose levels and times post-irradiation. Previous Raman data analysis was conducted using principal component analysis (PCA), which showed the ability to extract biological information of glycogen. In the current studies, the use of non-negative matrix factorization (NMF) allowed for the discovery of multiplexed biological information, specifically uncovering glycogen-like and lipid-like component bases. The corresponding scores of glycogen and previously unidentified lipids revealed the content variations of these two chemicals in the cellular data. The NMF decomposed glycogen and lipid-like bases were able to separate the cancer cell lines into radiosensitive and radioresistant groups. A further lipid phenotype investigation was also attempted by applying non-negative least squares (NNLS) to the lipid-like bases decomposed individually from three cell lines. Qualitative differences found in lipid weights for each lipid-like basis suggest the lipid phenotype differences in the three tested cancer cell lines. Collectively, this study demonstrates that the application of NMF and NNLS on RS data analysis to monitor ionizing radiation-induced cellular responses can yield multiplexed biological information on bio-response to RT not revealed by conventional chemometric approaches.

Macroautophagy/autophagy is a critical regulator of adaptive T cell immunity and homeostasis. However, the role of T cell autophagy in regulating antitumor immune responses is less clear. In a recent study, we showed that deletion of the essential autophagy genes Atg5, Atg14 , or Atg16l1 in host tissues dramatically impairs growth of autophagy-competent syngeneic tumors. We further demonstrated that CD8 + T cells lacking Atg5 acquire an effector memory phenotype and produce more IFNG/IFN-γ (interferon gamma) and TNF/TNF-α (tumor necrosis factor). These phenotypic changes are accompanied by enhanced glucose metabolism that results in alterations in histone methylation, and upregulation of glycolytic and immune response genes. In accordance with this, we observed control of tumor growth in autophagy-competent mice after adoptive transfer with a sub-therapeutic dose of atg5 -/- T cells. Collectively, we discovered a unique, cell-autonomous role for T cell autophagy in the metabolic control of antitumor immunity.

Research into factors affecting treatment response or survival in patients with cancer frequently involves cohorts that span the most common range of clinical outcomes, as such patients are most readily available for study. However, attention has turned to highly unusual patients who have exceptionally favourable or atypically poor responses to treatment and/or overall survival, with the expectation that patients at the extremes may provide insights that could ultimately improve the outcome of individuals with more typical disease trajectories. While clinicians can often recount surprising patients whose clinical journey was very unusual, given known clinical characteristics and prognostic indicators, there is a lack of consensus among researchers on how best to define exceptional patients, and little has been proposed for the optimal design of studies to identify factors that dictate unusual outcome. In this Opinion article, we review different approaches to identifying exceptional patients with cancer and possible study designs to investigate extraordinary clinical outcomes. We discuss pitfalls with finding these rare patients, including challenges associated with accrual of patients across different treatment centres and time periods. We describe recent molecular and immunological factors that have been identified as contributing to unusual patient outcome and make recommendations for future studies on these intriguing patients.

Tumor biobanks have become critical components of the cancer research infrastructure. Consideration of how to place appropriate values on tumor biobanks is important for all stakeholders. At the level of individual biobanks, value is important in determining how to contribute to, utilize, and fund biobanks. At the level of the research system, value is important in determining how to evaluate, rationalize, and sustain or modify the investments in this infrastructure. This review considers approaches and indicators for evaluation of a biobank with a particular focus on utilization, as one important indicator of value, from the perspective of the researcher and funder. The patterns of utilization and the influence of different phases and approaches of research, and types of biobank are described, as well as strategies for biobanks to increase utilization and therefore their value to research.

Autophagy is a cell survival process essential for the regulation of immune responses to infections. However, the role of T cell autophagy in anti-tumor immunity is less clear. Here, we demonstrate a cell-autonomous role for autophagy in the regulation of CD8 + T-cell-mediated control of tumors. Mice deficient for the essential autophagy genes Atg5, Atg14, or Atg16L1 display a dramatic impairment in the growth of syngeneic tumors. Moreover, T cells lacking Atg5 have a profound shift to an effector memory phenotype and produce greater amounts of interferon-γ (IFN-γ) and tumor necrosis factor α (TNF-α). Mechanistically, Atg5 -/- CD8 + T cells exhibit enhanced glucose metabolism that results in alterations in histone methylation, increases in H3K4me3 density, and transcriptional upregulation of both metabolic and effector target genes. Nonetheless, glucose restriction is sufficient to suppress Atg5-dependent increases in effector function. Thus, autophagy-dependent changes in CD8 + T cell metabolism directly regulate anti-tumor immunity., (Crown Copyright © 2019. Published by Elsevier Inc. All rights reserved.)

Infiltration of human cancers by T cells is generally interpreted as a sign of immune recognition, and there is a growing effort to reactivate dysfunctional T cells at such tumor sites 1 . However, these efforts only have value if the intratumoral T cell receptor (TCR) repertoire of such cells is intrinsically tumor reactive, and this has not been established in an unbiased manner for most human cancers. To address this issue, we analyzed the intrinsic tumor reactivity of the intratumoral TCR repertoire of CD8 + T cells in ovarian and colorectal cancer-two tumor types for which T cell infiltrates form a positive prognostic marker 2,3 . Data obtained demonstrate that a capacity to recognize autologous tumor is limited to approximately 10% of intratumoral CD8 + T cells. Furthermore, in two of four patient samples tested, no tumor-reactive TCRs were identified, despite infiltration of their tumors by T cells. These data indicate that the intrinsic capacity of intratumoral T cells to recognize adjacent tumor tissue can be rare and variable, and suggest that clinical efforts to reactivate intratumoral T cells will benefit from approaches that simultaneously increase the quality of the intratumoral TCR repertoire.

There is abundant evidence that tumor-infiltrating CD8 + T cells contribute positively to antitumor immunity; however, the role of tumor-infiltrating B cells (TIL-B) and plasma cells (PC) remains controversial, leading to differing opinions about whether immunotherapies should be designed to enhance or inhibit these cells. Through a comprehensive PubMed search, we reviewed publications with cohorts of 50 or more cases in which the prognostic value of TIL-B/PC was assessed by immunohistochemistry and/or gene-expression analysis. Sixty-nine studies representing 19 cancers met our review criteria. The large majority of studies assessed TIL-B by immunohistochemical detection of CD20. Of these, 50.0% reported a positive prognostic effect for CD20 + TIL-B, whereas the remainder found a neutral (40.7%) or negative (9.3%) effect. These differences in prognostic effect were not attributable to cancer type, other clinicopathologic factors, or differing technical approaches. The prognostic significance of TIL-B/PC was generally concordant with that of CD3 + and/or CD8 + T cells, and the prognostic effect of T cells was generally stronger when TIL-B and/or PC were also present. Additionally, 21 studies inferred the presence of TIL-B/PC from gene-expression data, and a large majority reported a positive prognostic effect. Although more studies are required involving additional cancer types and independent patient cohorts, the weight of evidence supports a positive role for TIL-B and PC in antitumor immunity, suggesting that enhancement of these responses should be considered in the design of cancer immunotherapies., (©2018 American Association for Cancer Research.)

Resident memory T cells (T RM ) are a recently identified subset of long-lived memory T cells that are characterized in terms of their unique surface phenotype combined with a non-recirculating pattern of localization to non-lymphoid, peripheral tissues. T RM have quickly become a key area of focus in understanding immune responses to microbial infection in so-called "barrier" tissues, and appear to be particularly critical for protection against repeat exposure at the same site. More recently, tumor-infiltrating T cells with canonical T RM features are being identified in human cancers, in particular cancers of epithelial origin, and their presence is broadly found to be associated with favorable long-term prognosis. Moreover, recent studies have shown that these "resident memory-like" tumor-infiltrating lymphocytes (referred to herein as TIL RM ) are uniquely activated in melanoma patients undergoing PD-1 directed checkpoint blockade therapy. Accordingly, there is much interest at present regarding the biology of these cells and their precise role in anti-cancer immunity. Herein, we review the current state of the literature regarding TIL RM with a specific emphasis on their specificity, origins, and relationship to conventional pathogen-specific T RM and speculate upon the way(s) in which they might contribute to improved prognosis for cancer patients. We discuss the growing body of evidence that suggests TIL RM may represent a population of bona-fide tumor-reactive T cells and the attractive possibility of leveraging this cell population for future immunotherapy.

Like all dividing cells, naïve T cells undergo a predictable sequence of events to enter the cell cycle starting from G 0 and progressing to G 1 , S and finally G 2 /M. This methodical series of steps ensures fidelity in the generation of two identical T cells during a single round of division. To achieve this, T cells must activate or inactivate metabolic pathways at discrete times during each phase of the cell cycle. This permits the generation of substrates to support biosynthesis, bioenergetics and the epigenetic changes required for proper differentiation and function. The precursors that feed into these pathways are often shared, highlighting the complex relationship between metabolism and cellular processes that are essential to lymphocytes. It is therefore not surprising that different T cell subtypes exhibit unique metabolic dependencies that change as they mature and go through specialized differentiation programmes. The importance of the influence of metabolism on T cells is underscored by the emerging field of cancer immunotherapy, where autologous T cells can be manufactured ex vivo then infused as a form of curative treatment for human cancers. This review will highlight some of the recent knowledge on T lymphocyte metabolism and give a perspective on the practical implications for cellular-based immunotherapy., (© 2018 Federation of European Biochemical Societies.)

To effectively build on the recent successes of immune checkpoint blockade, adoptive T cell therapy and cancer vaccines, it is critical to rationally design combination strategies that will increase and extend efficacy to a larger proportion of patients. For example, the combination of anti-cytotoxic T lymphocyte-associated antigen 4 (CTLA4) and anti-programmed cell death protein 1 (PD1) immune checkpoint inhibitors essentially doubles the response rate in certain patients with metastatic melanoma. However, given the heterogeneity of cancer, it seems likely that even more complex combinations of immunomodulatory agents may be required to obtain consistent, durable therapeutic responses against a broad spectrum of cancers. This carries serious implications in terms of toxicities for patients, feasibility for care providers and costs for health-care systems. A compelling solution is offered by oncolytic viruses (OVs), which can be engineered to selectively replicate within and destroy tumour tissue while simultaneously augmenting antitumour immunity. In this Opinion article, we argue that the future of immunotherapy will include OVs that function as multiplexed immune-modulating platforms expressing factors such as immune checkpoint inhibitors, tumour antigens, cytokines and T cell engagers. We illustrate this concept by following the trials and tribulations of tumour-reactive T cells from their initial priming through to the execution of cytotoxic effector function in the tumour bed. We highlight the myriad opportunities for OVs to help overcome critical barriers in the T cell journey, leading to new synergistic mechanisms in the battle against cancer.

The physiological changes that occur immediately following cancer surgeries initiate a chain of events that ultimately result in a short pro-, followed by a prolonged anti-, inflammatory period. Natural Killer (NK) cells are severely affected during this period in the recovering cancer patient. NK cells play a crucial role in anti-tumour immunity because of their innate ability to differentiate between malignant versus normal cells. Therefore, an opportunity arises in the aftermath of cancer surgery for residual cancer cells, including distant metastases, to gain a foothold in the absence of NK cell surveillance. Here, we describe the post-operative environment and how the release of sympathetic stress-related factors (e.g., cortisol, prostaglandins, catecholamines), anti-inflammatory cytokines (e.g., IL-6, TGF-β), and myeloid derived suppressor cells, mediate NK cell dysfunction. A snapshot of current and recently completed clinical trials specifically addressing NK cell dysfunction post-surgery is also discussed. In collecting and summarizing results from these different aspects of the surgical stress response, a comprehensive view of the NK cell suppressive effects of surgery is presented. Peri-operative therapies to mitigate NK cell suppression in the post-operative period could improve curative outcomes following cancer surgery., Competing Interests: In kind contribution of INergy (NCT02987296) and Tinzaparin (NCT01455831) from Enhanced Medical Nutrition and Leo Pharma, respectively.

Purpose: Biospecimens (e.g., tissues, bloods, fluids) are critical for translational cancer research to generate the necessary knowledge to guide implementation of precision medicine. Rising demand and the need for higher quality biospecimens are already evident. Experimental Design: The recent increase in requirement for biospecimen complexity in terms of linked biospecimen types, multiple preservation formats, and longitudinal data was explored by assessing trends in cancer research publications from 2000 to 2014. Results: A PubMed search shows that there has been an increase in both raw numbers and the relative proportion (adjusted for total numbers of articles in each period) of the subgroups of articles typically associated with the use of biospecimens and both dense treatment and/or outcomes data and multiple biospecimen formats. Conclusions: Increasing biospecimen complexity is a largely unrecognized and new pressure on cancer research biobanks. New approaches to cancer biospecimen resources are needed such as the implementation of more efficient and dynamic consent mechanisms, stronger participant involvement in biobank governance, development of requirements for registration of collections, and models to establish stock targets for biobanks. In particular, the latter two approaches would enable funders to establish a better balance between biospecimen supply and research demand, reduce expenditure on duplicate collections, and encourage increased efficiency of biobanks to respond to the research need for more complex cases. This in turn would also enable biobanks to focus more on quality and standardization that are surely factors in the even more important arena of research reproducibility. Clin Cancer Res; 23(4); 894-8. ©2016 AACR ., (©2016 American Association for Cancer Research.)

Owing to recent advances in genomic technologies, personalized oncology is poised to fundamentally alter cancer therapy. In this paradigm, the mutational and transcriptional profiles of tumors are assessed, and personalized treatments are designed based on the specific molecular abnormalities relevant to each patient's cancer. To date, such approaches have yielded impressive clinical responses in some patients. However, a major limitation of this strategy has also been revealed: the vast majority of tumor mutations are not targetable by current pharmacological approaches. Immunotherapy offers a promising alternative to exploit tumor mutations as targets for clinical intervention. Mutated proteins can give rise to novel antigens (called neoantigens) that are recognized with high specificity by patient T cells. Indeed, neoantigen-specific T cells have been shown to underlie clinical responses to many standard treatments and immunotherapeutic interventions. Moreover, studies in mouse models targeting neoantigens, and early results from clinical trials, have established proof of concept for personalized immunotherapies targeting next-generation sequencing identified neoantigens. Here, we review basic immunological principles related to T-cell recognition of neoantigens, and we examine recent studies that use genomic data to design personalized immunotherapies. We discuss the opportunities and challenges that lie ahead on the road to improving patient outcomes by incorporating immunotherapy into the paradigm of personalized oncology., (© The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Establishing the importance of biobanking in cancer research is important for research funders and for planning health research infrastructure. This study delineates the importance of biobanking to the cancer research landscape in Canada and relative to other forms of health research infrastructure., Methods: The Cancer Research Society (CRS) is a Canadian organization with a broad mission and national portfolio that funds studies across the spectrum of cancer research. We selected all 35 investigators who received CRS grants in the 2010/11 competition and then analyzed their publications from 2010 to 2014. Articles were categorized by overall research area, acknowledged source of funding, specific scientific focus, and the presence of any data that involved an 'indicator' (human biospecimens, cell lines, animal models, advanced microscopy, flow cell sorters, and next generation sequencing) of dependence on different kinds of health research infrastructures. Publications involving biobanking and utilizing biospecimens were further classified by biospecimen provenance and type of biospecimen used., Results: These investigators generated 502 (from a total of 749) papers that were related to the field of cancer research. Amongst 445 papers that contained primary data, we found no significant differences between CRS funded and 'other funded' papers in terms of biospecimen use, which occurred in 38% of articles. Overall biospecimens were mostly obtained directly from patients (17%), or indirectly from biorepositories (31%) and hospitals (46%). The proportions of studies using other tools was as follows: 54% cell lines, 32% animal models, 14% advanced microscopy, 14% flow sorters, and 8% next generation sequencing. The spectrum of research was very similar to the overall profile of cancer research in Canada in 2010., Conclusions: This study suggests that biorepositories that coordinate the activity of biobanking rank amongst the most important of established health research infrastructures as contributors to research publications.

Tumors and the immune system are intertwined in a competition where tilting the fine balance between tumor-specific immunity and tolerance can ultimately decide the fate of the host. Defensive and suppressive immunological responses to cancer are exquisitely sensitive to metabolic features of rapidly growing tumors, such as hypoxia, low nutrient availability, and aberrant growth factor signaling. As a result, clinical therapies impacting these properties change the in situ antitumor immune response by virtue of disrupting the tumor environment. To compensate for disruptions in cellular metabolism, cells activate autophagy to promote survival. On the basis of this notion, strategies designed to block autophagy in tumor cells are currently being tested in several human clinical trials. However, therapies that impair tumor metabolism must also take into account their effect on lymphocytes activated in the immune response to cancer. Given that a strong antitumor immune response is a positive prognostic factor in overall patient survival, identifying ways to block essential processes in tumor cells and suppressive immune cells while promoting those that are important for a robust immune response are of critical importance. Herein, we review the effects of anti-cancer agents that impact metabolism administered concurrently with autophagy inhibitors on immune cells and consider the implications for patient response to therapy., (© 2012 John Wiley & Sons A/S.)

CD8+ tumor-infiltrating lymphocytes (TIL) are associated with survival in a variety of cancers. A second subpopulation of TIL, defined by forkhead box protein P3 (FoxP3) expression, has been reported to inhibit tumor immunity, resulting in decreased patient survival. On the basis of this premise, several groups are attempting to deplete FoxP3+ T cells to enhance tumor immunity. However, recent studies have challenged this paradigm by showing that FoxP3+ T cells exhibit heterogeneous phenotypes and, in some cohorts, are associated with favorable prognosis. These discrepant results could arise from differences in study methodologies or the biologic properties of specific cancer types. Here, we conduct the first systematic review of the prognostic significance of FoxP3+ T cells across nonlymphoid cancers (58 studies from 16 cancers). We assessed antibody specificity, cell-scoring strategy, multivariate modeling, use of single compared with multiple markers, and tumor site. Two factors proved important. First, when FoxP3 was combined with one additional marker, double-positive T cells were generally associated with poor prognosis. Second, tumor site had a major influence. FoxP3+ T cells were associated with poor prognosis in hepatocellular cancer and generally good prognosis in colorectal cancer, whereas other cancer types were inconsistent or understudied. We conclude that FoxP3+ T cells have heterogeneous properties that can be discerned by the use of additional markers. Furthermore, the net biologic effects of FoxP3+ T cells seem to depend on the tumor site, perhaps reflecting microenvironmental differences. Thus, depletion of FoxP3+ T cells might enhance tumor immunity in some patient groups but be detrimental in others.

Tumor-infiltrating CD8(+) T cells are strongly associated with patient survival in a wide variety of human cancers. Less is known about tumor-infiltrating CD20(+) B cells, which often colocalize with T cells, sometimes forming organized lymphoid structures. In autoimmunity and organ transplantation, T cells and B cells collaborate to generate potent, unrelenting immune responses that can result in extensive tissue damage and organ rejection. In these settings, B cells enhance T cell responses by producing Abs, stimulatory cytokines, and chemokines, serving as local APCs, and organizing the formation of tertiary lymphoid structures that sustain long-term immunity. Thus, B cells are an important component of immunological circuits associated with persistent, rampant tissue destruction. Engagement of tumor-reactive B cells may be an important condition for generating potent, long-term T cell responses against cancer.