Complement c5a receptor facilitates cancer metastasis by altering t-cell responses in the metastatic niche

The impact of complement on cancer metastasis has not been well studied. In this report, we demonstrate in a preclinical mouse model of breast cancer that the complement anaphylatoxin C5a receptor (C5aR) facilitates metastasis by suppressing effector CD8(+) and CD4(+) T-cell responses in the lungs. Mechanisms of this suppression involve recruitment of immature myeloid cells to the lungs and regulation of TGF beta and IL10 production in these cells. TGF beta and IL10 favored generation of T regulatory cells (T-reg) and Th2-oriented responses that rendered CD8(+) T cells dysfunctional. Importantly, pharmacologic blockade of C5aR or its genetic ablation in C5aR-deficient mice were sufficient to reduce lung metastases. Depletion of CD8(+) T cells abolished this beneficial effect, suggesting that CD8(+) T cells were responsible for the effects of C5aR inhibition. In contrast to previous findings, we observed that C5aR signaling promoted T-reg generation and suppressed T-cell responses in organs where metastases arose. Overall, our findings indicated that the immunomodulatory functions of C5aR are highly context dependent. Furthermore, they offered proof-of-concept for complement-based immunotherapies to prevent or reduce cancer metastasis. (C) 2014 AACR

The ribosomal protein S19 suppresses antitumor immune responses via the complement C5a receptor 1

Relatively little is known about factors that initiate immunosuppression in tumors and act at the interface between tumor cells and host cells. In this article, we report novel immunosuppressive properties of the ribosomal protein S19 (RPS19), which is upregulated in human breast and ovarian cancer cells and released from apoptotic tumor cells, whereupon it interacts with the complement C5a receptor 1 expressed on tumor infiltrating myeloid-derived suppressor cells. This interaction promotes tumor growth by facilitating recruitment of these cells to tumors. RPS19 also induces the production of immunosuppressive cytokines, including TGF-b, by myeloid-derived suppressor cells in tumor-draining lymph nodes, leading to T cell responses skewed toward Th2 phenotypes. RPS19 promotes generation of regulatory T cells while reducing infiltration of CD8+ T cells into tumors. Reducing RPS19 in tumor cells or blocking the C5a receptor 1-RPS19 interaction decreases RPS19-mediated immunosuppression, impairs tumor growth, and delays the development of tumors in a transgenic model of breast cancer. This work provides initial preclinical evidence for targeting RPS19 for anticancer therapy enhancing antitumor T cell responses

Organ-specific heterogeneity in tumor-infiltrating immune cells and cancer antigen expression in primary and autologous metastatic lung adenocarcinoma

Background Tumor immune microenvironment (TIME) and cancer antigen expression, key factors for the development of immunotherapies, are usually based on the data from primary tumors due to availability of tissue for analysis; data from metastatic sites and their concordance with primary tumor are lacking. Although of the same origin from primary tumor, organ-specific differences in the TIME in metastases may contribute to discordant responses to immune checkpoint inhibitor agents. In immunologically ‘cold’ tumors, cancer antigen-targeted chimeric antigen receptor (CAR) T-cell therapy can promote tumor-infiltrating lymphocytes; however, data on distribution and intensity of cancer antigen expression in primary tumor and matched metastases are unavailable.Methods We performed a retrospective review of a prospectively maintained database of patients who had undergone curative resection of pathological stage I–III primary lung adenocarcinoma from January 1995 to December 2012 followed by metastatic recurrence and resection of metastatic tumor (n=87). We investigated the relationship between the primary tumor and metastasis TIME (ie, tumor-infiltrating lymphocytes, tumor-associated macrophages, and programmed death-ligand 1 (PD-L1)) and cancer antigen expression (ie, mesothelin, CA125, and CEACAM6) using multiplex immunofluorescence.Results Brain metastases (n=36) were observed to have fewer tumor-infiltrating lymphocytes and greater PD-L1-negative tumor-associated macrophages compared with the primary tumor (p<0.0001); this relatively inhibitory TIME was not observed in other metastatic sites. In one in three patients, expression of PD-L1 is discordant between primary and metastases. Effector-to-suppressor (E:S) cell ratio, median effector cells (CD20+ and CD3+) to suppressor cells (CD68/CD163+) ratio, in metastases was not significantly different between patients with varying E:S ratios in primary tumors. Cancer antigen distribution was comparable between primary and metastases; among patients with mesothelin, cancer antigen 125, or carcinoembryonic antigen adhesion molecule 6 expression in the primary tumor, the majority (51%–75%) had antigen expression in the metastases; however, antigen-expression intensity was heterogenous.Conclusions In patients with lung adenocarcinoma, brain metastases, but not other sites of metastases, exhibited a relatively immune-suppressive TIME; this should be considered in the context of differential response to immunotherapy in brain metastases. Among patients with cancer antigen expression in the primary tumor, the majority had antigen expression in metastases; these data can inform the selection of antigen-targeted CARs to treat patients with metastatic lung adenocarcinoma