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Objectives The immune effects of EGFR tyrosine kinase inhibitors (EGFR-TKIs) are poorly understood. Identifying immune biomarkers could guide patient selection and optimisation of EGFR-TKI-immunotherapy combinations. Materials and methods 33 patients with NSCLC treated with an EGFR-TKI were prospectively enrolled. Peripheral blood mononuclear cells were collected pre-treatment, and after 1, 3 and 8 weeks. Flow cytometry was used to identify immune cell subsets, including PD-1 and PD-L1 expressing T cells. Immune parameters were correlated with clinical outcomes. Results Compared to healthy donors ( n = 10), patients had higher pre-treatment proportions of proliferating and PD-L1 + CD3 + T cells ( p < 0.001). Compared to patients with an EGFR mutation ( n = 12), patients without a known mutation ( n = 21) had higher proportions of proliferating CD4 + and PD-L1 + CD3 + T cells ( p = 0.03). There was a significant increase in PD-L1 + T cells after 1 week of EGFR-TKI in patients whose disease progressed compared to non-progressors. Patients with higher PD-L1 + CD3 + T cells at 1-week were more likely to progress (OR 30.3, p < 0.01) and had shorter PFS (1.6 vs. 8.8 m; p < 0.01) and OS (3.8 vs 23.2 m; p < 0.001) than those with fewer PD-L1 + CD3 + T cells. On multivariate analysis, high PD-L1 + CD3 + T cells was the only independent predictor for PFS (HR 3.7, p = 0.01), while for OS independent predictors were high PD-L1 + CD3 + T cells (HR 6.5, p < 0.01) and EGFR-negative status (HR 3.3, p = 0.04). Conclusions There was a significant correlation between PD-L1 expression on peripheral T cells and clinical outcomes in EGFR-TKI-treated NSCLC. This warrants further validation as a blood-based biomarker that may identify candidates for PD-1 inhibitors or immunotherapy-EGFR-TKI combinations. [ABSTRACT FROM AUTHOR]

Cross-presentation of tumor antigen is essential for efficient priming of naïve CD8+ T lymphocytes and induction of effective anti-tumor immunity. We hypothesized that the subcellular location of a tumor antigen could affect the efficiency of cross-presentation, and hence the outcome of anti-tumor responses to that antigen. We compared cross-presentation of a nominal antigen expressed in the nuclear, secretory, or cytoplasmic compartments of B16 melanoma tumors. All tumors expressed similar levels of the antigen. The antigen was cross-presented from all compartments but when the concentration was low, nuclear antigen was less efficiently cross-presented than antigen from other cellular locations. The efficiency of cross-presentation of the nuclear antigen was improved following chemotherapy-induced tumor cell apoptosis and this correlated with an increase in the proportion of effector CTL. These data demonstrate that chemotherapy improves nuclear tumor antigen cross-presentation and could be important for anti-cancer immunotherapies that target nuclear antigens. [ABSTRACT FROM AUTHOR]

Abstract: Cytotoxic chemotherapy not only affects the tumour but also targets dividing lymphocytes, the very cells required to develop an immune response. Hence, chemo- and immunotherapy have been seen as antagonistic. It is now clear that the way a chemotherapeutic drug kills a tumour cell determines how that dying cell interacts with the immune system and whether the interaction leads to an immune response. Chemotherapy also depletes regulatory T cells, potentially enhancing immune responses. Furthermore, lymphodepletion triggers homeostatic T cell reconstitution, creating new populations of pre-T cells that need education in the thymic environment. Post-chemotherapy immune system reconstitution may provide a unique opportunity for therapeutic intervention by shaping the repertoire towards reactivity to tumour antigens. An understanding of the underlying cellular and immunological events in both animal models and patients undergoing chemotherapy will guide decisions about which immunomodulatory approaches may be effective with different cytostatic drugs and hence to develop appropriate scheduling for integration of the treatment modalities. [Copyright &y& Elsevier]

This article discusses how recent data have altered the way we understand how dying tumour cells, particularly those killed by chemotherapy, engage with antitumour immune responses. These data have significant implications for the development of new protocols combining chemotherapy with immunotherapy, indicating an exciting potential for therapeutic synergy with general applicability to many cancer types. [ABSTRACT FROM AUTHOR]

Surgical resection of cancer remains the frontline therapy for millions of patients annually, but post-operative recurrence is common, with a relapse rate of around 45% for non-small cell lung cancer. The tumour draining lymph nodes (dLN) are resected at the time of surgery for staging purposes, and this cannot be a null event for patient survival and future response to immune checkpoint blockade treatment. This project investigates cancer surgery, lymphadenectomy, onset of metastatic disease, and response to immunotherapy in a novel model that closely reflects the clinical setting. In a murine metastatic lung cancer model, primary subcutaneous tumours were resected with associated dLNs remaining intact, completely resected or partially resected. Median survival after surgery was significantly shorter with complete dLN resection at the time of surgery (49 days (95%CI)) compared to when lymph nodes remained intact (> 88 days; p < 0.05). Survival was partially restored with incomplete lymph node resection and CD8 T cell dependent. Treatment with aCTLA4 whilst effective against the primary tumour was ineffective for metastatic lung disease. Conversely, aPD-1/aCD40 treatment was effective in both the primary and metastatic disease settings and restored the detrimental effects of complete dLN resection on survival. In this pre-clinical lung metastatic disease model that closely reflects the clinical setting, we observe decreased frequency of survival after complete lymphadenectomy, which was ameliorated with partial lymph node removal or with early administration of aPD-1/aCD40 therapy. These findings have direct relevance to surgical lymph node resection and adjuvant immunotherapy in lung cancer, and perhaps other cancer, patients. [ABSTRACT FROM AUTHOR]

Dexamethasone is a synthetic glucocorticoid commonly used for the prevention and management of side effects in cancer patients undergoing chemotherapy. While it is effective as an anti-emetic and in preventing hypersensitivity reactions, dexamethasone depletes peripheral blood lymphocytes and impacts immune responses. The effect of dexamethasone on the number and quality of tumour-infiltrating leukocytes has not been reported. To address this, we calibrated the dose in two different strains of mice to achieve the same extent of peripheral blood lymphocyte depletion observed in patients with cancer. Doses that caused analogous depletion of T and B lymphocytes and NK cells from the peripheral blood, elicited no change in these populations within the tumour. The expression of immune checkpoint molecules PD-1, OX40, GITR and TIM3 on tumour-infiltrating lymphocytes was not altered. We found that dexamethasone had a small but significant deleterious impact on weakly efficacious chemoimmunotherapy but had no effect when the protocol was highly efficacious. Based on these results, we predict that dexamethasone will have a modest negative influence on the overall effectiveness of chemoimmunotherapy treatment. [ABSTRACT FROM AUTHOR]

The glucocorticoid (GC) steroid dexamethasone (Dex) is used as a supportive care co-medication for cancer patients undergoing standard care pemetrexed/platinum doublet chemotherapy. As trials for new cancer immunotherapy treatments increase in prevalence, it is important to track the immunological changes induced by co-medications commonly used in the clinic, but not specifically included in trial design or in pre-clinical models. Here, we document a number of Dex -induced immunological effects, including a large-scale lymphodepletive effect particularly affecting CD4+T cells but also CD8+T cells. The proportion of regulatory T cells within the CD4+compartment did not change after Dex was administered, however a significant increase in proliferation and activation of regulatory T cells was observed. We also noted Dex -induced proportional changes in dendritic cell (DC) subtypes. We discuss these immunological effects in the context of chemoimmunotherapy strategies, and suggest a number of considerations to be taken into account when designing future studies where Dex and other GCs may be in use. [ABSTRACT FROM PUBLISHER]

Background Tumor debulking surgery followed by adjuvant chemotherapy or radiotherapy is a standard treatment for many solid malignancies. Although this approach can be effective, it often has limited success against recurrent or metastatic cancers and new multimodality approaches are needed. Adjuvant immunotherapy is another potentially effective approach. We therefore tested the efficacy of the TLR7 agonist imiquimod (IMQ) combined with agonistic anti-CD40 as adjuvant in an incomplete debulking surgical model of solid cancer. We tested the efficacy of adjuvant imiquimod (IMQ) combined with agonistic anti-CD40 in an incomplete debulking model of malignant mesothelioma. Methods Established subcutaneous murine ABA-HA mesothelioma tumors in BALB/c mice were surgically debulked by 75% and treated with either: i) saline; ii) intratumoral IMQ; iii) systemic anti-CD40 antibody, or using a combination of IMQ and anti-CD40. Tumour growth and survival were monitored, and the role of anti-tumor CD4 and CD8 T cells in therapeutic responses was determined. Results The combination therapy of partial debulking surgery, IMQ and anti-CD40 significantly delayed tumor growth in a CD8 T cell dependent manner, and promoted tumor regression in 25% of animals with establishment of immunological memory. This response was associated with an increase in ICOS+ CD8 T cells and tumor-specific CTL activity in tumor draining lymph nodes along with an increase in ICOS+ CD8 T cells in responding tumours. Conclusions We show that the post-surgical environment can be significantly altered by the co- administration of adjuvant IMQ and anti-CD40, resulting in strong, systemic anti-tumor activity. Both adjuvants are available for clinical use/trial, hence this treatment regimen has clear translational potential. [ABSTRACT FROM AUTHOR]

A correction to this paper has been published: https://doi.org/10.1007/s00262-021-02970-z [ABSTRACT FROM AUTHOR]

Several chemotherapeutics exert immunomodulatory effects. One of these is the nucleoside analogue gemcitabine, which is widely used in patients with lung cancer, ovarian cancer, breast cancer, mesothelioma and several other types of cancer, but with limited efficacy. We hypothesized that the immunopotentiating effects of this drug are partly restrained by the inhibitory T cell molecule CTLA-4 and thus could be augmented by combining it with a blocking antibody against CTLA-4, which on its own has recently shown beneficial clinical effects in the treatment of patients with metastatic melanoma. Here we show, using two non-immunogenic murine tumor models, that treatment with gemcitabine chemotherapy in combination with CTLA-4 blockade results in the induction of a potent anti-tumor immune response. Depletion experiments demonstrated that both CD4+ and CD8+ T cells are required for optimal therapeutic effect. Mice treated with the combination exhibited tumor regression and long-term protective immunity. In addition, we show that the efficacy of the combination is moderated by the timing of administration of the two agents. Our results show that immune checkpoint blockade and cytotoxic chemotherapy can have a synergistic effect in the treatment of cancer. These results provide a basis to pursue combination therapies with anti-CTLA-4 and immunopotentiating chemotherapy and have important implications for future studies in cancer patients. Since both drugs are approved for use in patients our data can be immediately translated into clinical trials. [ABSTRACT FROM AUTHOR]

Agonistic anti-CD40 antibody is a potent stimulator of anti-tumor immune responses due to its action on both immune and tumor cells. It has the ability to 'precondition' dendritic cells, allowing them to prime effective cytotoxic T-cell responses. Thus, anti-CD40 antibody provides an ideal therapy for combination with traditional cancer treatments (i.e., chemotherapy, surgery) in order to elicit immune-mediated anti-tumor effects. This review summarizes the mechanisms of action of agonistic anti-CD40, the use of mouse models to investigate its effects and combinations with other therapies in vivo, and current clinical trials combining humanized anti-CD40 antibody with chemotherapy and/or other immunotherapies. [ABSTRACT FROM AUTHOR]

Mesothelioma is an aggressive asbestos induced cancer with extremely poor prognosis and limited treatment options. Immune checkpoint blockade (ICPB) has demonstrated effective therapy in melanoma and is now being applied to other cancers, including mesothelioma. However, the efficacy of ICPB and which immune checkpoint combinations constitute the best therapeutic option for mesothelioma have yet to be fully elucidated. Here, we used our well characterised mesothelioma tumour model to investigate the efficacy of different ICBP treatments to generate effective therapy for mesothelioma. We show that tumour resident regulatory T cell co-express high levels of CTLA-4, OX40 and GITR relative to T effector subsets and that these receptors are co-expressed on a large proportion of cells. Targeting any of CTLA-4, OX40 or GITR individually generated effective responses against mesothelioma. Furthermore, the combination of αCTLA-4 and αOX40 was synergistic, with an increase in complete tumour regressions from 20% to 80%. Other combinations did not synergise to enhance treatment outcomes. Finally, an early pattern in T cell response was predictive of response, with activation status and ICP receptor expression profile of T effector cells harvested from tumour and dLN correlating with response to immunotherapy. Taken together, these data demonstrate that combination ICPB can work synergistically to induce strong, durable immunity against mesothelioma in an animal model. [ABSTRACT FROM AUTHOR]