Carcinoma-associated fibroblasts (CAFs) are abundant and heterogeneous stromal cells in tumor microenvironment that are critically involved in cancer progression. Here, we demonstrate that two cell-surface molecules, CD10 and GPR77, specifically define a CAF subset correlated with chemoresistance and poor survival in multiple cohorts of breast and lung cancer patients. CD10GPR77 CAFs promote tumor formation and chemoresistance by providing a survival niche for cancer stem cells (CSCs). Mechanistically, CD10GPR77 CAFs are driven by persistent NF-κB activation via p65 phosphorylation and acetylation, which is maintained by complement signaling via GPR77, a C5a receptor. Furthermore, CD10GPR77 CAFs promote successful engraftment of patient-derived xenografts (PDXs), and targeting these CAFs with a neutralizing anti-GPR77 antibody abolishes tumor formation and restores tumor chemosensitivity. Our study reveals a functional CAF subset that can be defined and isolated by specific cell-surface markers and suggests that targeting the CD10GPR77 CAF subset could be an effective therapeutic strategy against CSC-driven solid tumors.

Activation-induced cell death (AICD) of T lymphocytes can be exploited by cancers to escape immunological destruction. We demonstrated that tumor-specific cytotoxic T lymphocytes (CTLs) and type 1 helper T (T1) cells, rather than type 2 helper T cells and regulatory T cells, were sensitive to AICD in breast and lung cancer microenvironments. NKILA, an NF-κB-interacting long noncoding RNA (lncRNA), regulates T cell sensitivity to AICD by inhibiting NF-κB activity. Mechanistically, calcium influx in stimulated T cells via T cell-receptor signaling activates calmodulin, thereby removing deacetylase from the NKILA promoter and enhancing STAT1-mediated transcription. Administering CTLs with NKILA knockdown effectively inhibited growth of breast cancer patient-derived xenografts in mice by increasing CTL infiltration. Clinically, NKILA overexpression in tumor-specific CTLs and T1 cells correlated with their apoptosis and shorter patient survival. Our findings underscore the importance of lncRNAs in determining tumor-mediated T cell AICD and suggest that engineering lncRNAs in adoptively transferred T cells might provide a novel antitumor immunotherapy.

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Tumor-associated macrophages (TAMs) are the most abundant inflammatory infiltrates in the tumor stroma. TAMs promote tumor growth by suppressing immunocompetent cells, including neovascularization and supporting cancer stem cells. In the chapter, we discuss recent efforts in reprogramming or inhibiting tumor-protecting properties of TAMs, and developing potential strategies to increase the efficacy of breast cancer treatment.

The heterogeneity of cancer-associated fibroblasts (CAFs) might be ascribed to differences in origin. CD10 and GPR77 have been reported to identify a chemoresistance-inducing CAF subset in breast cancer. However, the precise mechanism for the formation of the CD10+GPR77+ CAFs remains unknown. In this study, we found that CCL18 expression was positively correlated with the density of CD10+GPR77+ CAFs in breast cancer and associated with a poor response to chemotherapy. Moreover, CCL18 secreted by tumor-associated macrophages (TAMs) activated a CD10+GPR77+ CAF phenotype in normal breast-resident fibroblasts (NBFs), which could then enrich cancer stem cells (CSCs) and induce chemoresistance in breast cancer cells. Mechanistically, CCL18 activated NF-κB signaling via PITPNM3 and thus enhanced the production of IL-6 and IL-8. Furthermore, intratumoral CCL18 injection significantly induced the activation of NBFs and the chemoresistance of xenografts in vivo. In addition, targeting CCL18 by anti-CCL18 antibody could inhibit the formation of CD10+GPR77+ CAFs and recover the chemosensitivity in vivo, leading to effective tumor control. Collectively, these findings reveal that inflammatory signaling crosstalk between TAMs and fibroblasts is responsible for the formation of the CD10+GPR77+ CAFs, suggesting CCL18–PITPNM3 signaling is a potential therapeutic target to block the activation of this specific CAF subtype and tumor chemoresistance.

The therapeutic efficacy of chemotherapy is in part a result of its ability to enhance adaptive antitumor immune responses. However, tumor cells exploit various evasion mechanisms to escape the immune attack and blunt chemosensitivity. Herein, we report that through single-cell profiling of the tumor immune microenvironment we identified a subset of CD161-overexpressing CD8+ T cells enriched in chemoresistant tumors. CD161 engagement repressed the calcium influx and cytolytic capacity of CD8+ T cells through acid sphingomyelinase (ASM) activation and ceramide generation. Targeting CD161 in adoptively transferred cytotoxic T lymphocytes enhanced antitumor immunity and reversed chemoresistance in patient-derived xenografts in vivo. Clinically, CD161 expression on CD8+ T cells was associated with chemoresistance and shortened patient survival. Our findings provide insights into novel immunosuppressive mechanisms in chemoresistance and highlight targeting CD161 as a potential therapeutic strategy.