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The analysis of peripheral blood mononuclear cells (PBMCs) by flow cytometry holds promise as a platform for immune checkpoint inhibition (ICI) biomarker identification. Our aim was to characterize the systemic immune compartment in resectable esophageal adenocarcinoma patients treated with neoadjuvant ICI therapy. In total, 24 patients treated with neoadjuvant chemoradiotherapy (nCRT) and anti-PD-L1 (atezolizumab) from the PERFECT study (NCT03087864) were included and 26 patients from a previously published nCRT cohort. Blood samples were collected at baseline, on-treatment, before and after surgery. Response groups for comparison were defined as pathological complete responders (pCR) or patients with pathological residual disease (non-pCR). Based on multicolor flow cytometry of PBMCs, an immunosuppressive phenotype was observed in the non-pCR group of the PERFECT cohort, characterized by a higher percentage of regulatory T cells (Tregs), intermediate monocytes, and a lower percentage of type-2 conventional dendritic cells. A further increase in activated Tregs was observed in non-pCR patients on-treatment. These findings were not associated with a poor response in the nCRT cohort. At baseline, immunosuppressive cytokines were elevated in the non-pCR group of the PERFECT study. The suppressive subsets correlated at baseline with a Wnt/β-Catenin gene expression signature and on-treatment with epithelial–mesenchymal transition and angiogenesis signatures from tumor biopsies. After surgery monocyte activation (CD40), low CD8+Ki67+ T cell rates, and the enrichment of CD206+ monocytes were related to early recurrence. These findings highlight systemic barriers to effective ICI and the need for optimized treatment regimens. [ABSTRACT FROM AUTHOR]

Simple Summary: Natural Killer (NK) cells are innate lymphocytes that play an important role in the immune response against cancer. Their activity is controlled by a balance of inhibitory and activating receptors, which in cancer can be skewed to favor their suppression in support of immune escape. It is therefore imperative to find ways to optimize their antitumor functionality. In this review, we explore and discuss how their activity influences, or even mediates, the efficacy of various anti-cancer therapies and, vice versa, how their activity can be affected by these therapies. Knowledge of the mechanisms underlying these observations could provide rationales for combining anti-cancer treatments with strategies enhancing NK cell function in order to improve their therapeutic efficacy. Natural Killer (NK) cells are innate immune cells with the unique ability to recognize and kill virus-infected and cancer cells without prior immune sensitization. Due to their expression of the Fc receptor CD16, effector NK cells can kill tumor cells through antibody-dependent cytotoxicity, making them relevant players in antibody-based cancer therapies. The role of NK cells in other approved and experimental anti-cancer therapies is more elusive. Here, we review the possible role of NK cells in the efficacy of various anti-tumor therapies, including radiotherapy, chemotherapy, and immunotherapy, as well as the impact of these therapies on NK cell function. [ABSTRACT FROM AUTHOR]

Previous vaccination studies in patients with castration-resistant prostate cancer (CRPC) showed improved survival without prolongation of progression-free survival (PFS). This might be explained by enhanced efficacy of subsequent therapies because of heightened immune status. We therefore evaluated the efficacy of chemotherapy in CRPC patients after immunotherapy. We retrospectively analyzed 28 patients who were treated with ipilimumab and GVAX, an allogeneic vaccine, and 21 patients who were randomized to GVAX or no vaccination. To study whether immune status was related to the efficacy of chemotherapy, frequencies of myeloid and lymphocyte subsets were determined. Of 28 patients treated with GVAX and ipilimumab, 23 patients received docetaxel and 13 patients mitoxantrone. Median PFS after docetaxel was 6.4 mo (range 0.8–11.2), while median PFS after mitoxantrone was markedly longer than expected (4.8 mo; range 1.4–13.7). High CD8+ICOS+Tcell/Treg and pDC/mMDSC ratios were associated with relatively long PFS after mitoxantrone, suggesting a correlation between activated immune status and benefit of mitoxantrone. Analysis of 21 patients, randomized to GVAX or not, revealed a median PFS after docetaxel of 9.9 mo for vaccinated patients and 7.1 mo for unvaccinated patients. Interestingly, PFS after mitoxantrone (n = 14) was significantly longer in vaccinated patients as compared to controls (5.9 vs. 1.6 mo,p = 0.0048). In conclusion, mitoxantrone seems more effective in CRPC patients after immunotherapy, which may be related to the immune-stimulating effect of mitoxantrone in patients with heightened antitumor immunity. As this was a retrospective study with limited sample size, prospective studies are warranted to definitively show proof of principle. [ABSTRACT FROM AUTHOR]

Chemotherapy (CT), radiotherapy (RT), and chemoradiotherapy (CRT) are able to alter the composition of the tumor immune microenvironment (TIME). Understanding the effect of these modalities on the TIME could aid in the development of improved treatment strategies. Our aim was to systematically review studies investigating the influence of CT, RT or CRT on different TIME markers. The EMBASE (Ovid) and PubMed databases were searched until January 2019 for prospective or retrospective studies investigating the dynamics of the local TIME in cancer patients (pts) treated with CT, RT or CRT, with or without targeted agents. Studies could either compare baseline and follow-up specimens - before and after treatment - or a treated versus an untreated cohort. Studies were included if they used immunohistochemistry and/or flow cytometry to assess the TIME. In total we included 110 studies (n = 8850 pts), of which n = 89 (n = 6295 pts) compared pre-treatment to post-treatment specimens and n = 25 (n = 2555 pts) a treated versus an untreated cohort (4 studies conducted both comparisons). For several tumor types (among others; breast, cervical, esophageal, ovarian, rectal, lung mesothelioma and pancreatic cancer) remodeling of the TIME was observed, leading to a potentially more immunologically active microenvironment, including one or more of the following: an increase in CD3 or CD8 lymphocytes, a decrease in FOXP3 Tregs and increased PD-L1 expression. Both CT and CRT were able to immunologically alter the TIME. The TIME of several tumor types is significantly altered after conventional therapy creating opportunities for concurrent or sequential immunotherapy. [ABSTRACT FROM AUTHOR]