Cancer immunosurveillance by gut T cells

The immune system has the ability to destroy aggressive malignancies when called into action by immunotherapy (1). Additionally, the gut microbiota critically influence systemic immune responses and the efficacy of cancer immunotherapies such as immune checkpoint blockade (ICB) (2, 3). However, how gut microbiota or gut-primed immune cells regulate peripheral antitumor immune responses and ICB efficacy remains unclear. On page 1027 of this issue, Fidelle et al. (4), along with a study by Feliu et al. (5), reveal a critical role for gut-derived T cells in extraintestinal cancer immunosurveillance. These enterotropic T cells, which are primed in gut-draining lymph nodes, can migrate to distant tumors, where they substantially alter the tumor microenvironment (TME) and response to ICB. This unexpected extraintestinal role of gut T cells informs mechanisms of how antibiotics affect ICB responses, inspires therapeutic strategies to manipulate the TME, and may yield new biomarkers to guide ICB use.

The gut represents a distinct barrier site that is constantly exposed to microbes and dietary antigens, which requires a careful balancing of effector and suppressive immune responses to maintain intestinal homeostasis (6). Disruptions to the composition and homeostasis of the gut microbiota, referred to as dysbiosis, contribute to ICB resistance in tumor-bearing mice (2, 3). Accordingly, several studies have reported that antibiotic treatment can negatively affect patient responses to ICB in diverse cancer types, including melanoma, renal cell carcinoma, and non–small cell lung cancer (3, 7), emphasizing the systemic immunoregulatory role of the gut. Furthermore, gut-primed, enterotropic T cells that express the gut-homing α4β7 integrin influence extraintestinal immune responses in the context of inflammatory bowel disease (8). However, whether enterotropic T cells influence tumor immunosurveillance and whether gut microbiota are involved in this process remain unclear.

ICB boosts antitumor immune responses by interfering with regulatory immune checkpoints that restrain cancer immunosurveillance. Fidelle et al. investigated the mechanisms underpinning reduced ICB efficacy in mice after broad-spectrum antibiotic treatment. In a mouse model of fibrosarcoma, they found that after antibiotic treatment, gut recolonization by several species of the genus Enterocloster instigated ICB resistance. Moreover, they found that metabolites produced by Enterocloster species disrupt intestinal homing of α4β7 integrin–expressing T cells by reducing expression of the α4β7 ligand, mucosal addressin cell adhesion molecule 1 (MAdCAM-1), on gut endothelial cells that line intestinal vasculature. The loss of MAdCAM-1 expression triggered an exodus of α4β7 integrin–expressing T cells from the ileal lamina propria and gut-associated lymphoid tissues to tumor-draining lymph nodes of distant fibrosarcoma tumors that were implanted subcutaneously in mice.

Although diverse CD4⁺ and CD8⁺ T cell populations were found to move from the gut to tumors, Fidelle et al. identified a key role for interleukin-17A (IL-17A)–producing CD4⁺ T regulatory 17 (T_reg17) cells in suppressing antitumor immune responses and ICB efficacy in antibiotic-treated mice. Notably, genetic or pharmacological disruption of the MAdCAM-1–α4β7 integrin interaction also interfered with ICB efficacy in mice, and the deleterious effects of antibiotic treatment could be abrogated by IL-17A neutralization in vivo or by steering enterotropic T_reg17 cells away from the tumor. Although the precise mechanisms by which enterotropic T_reg17 cells blunt systemic cancer immunosurveillance are unclear, enterotropic T_reg17 cells in the tumor and tumor-draining lymph nodes expressed genes encoding several canonical immunosuppressive molecules such as IL-10, CD39, and CD73, which likely contributed to an immunosuppressive TME.

Fidelle et al. also found that soluble MAdCAM-1 detected in the blood positively correlates with ileal MAdCAM-1 expression in mice and dysbiosis in non–small cell lung cancer patients. Low amounts of circulating soluble MAdCAM-1 were associated with ICB resistance in patients with advanced bladder, kidney, and lung cancer, potentially reflecting the mobilization of suppressive T_reg17 cells from the gut. These findings indicate that soluble MAdCAM-1 concentrations may be useful in guiding ICB treatment and point to the MAdCAM-1–α4β7 integrin axis as a potential target for improving ICB efficacy in the context of dysbiosis.

About 25% of colorectal cancer patients are diagnosed with aggressive metastatic disease, and there are limited effective treatment options (9). To investigate how local, gut-derived immune responses influence systemic immunosurveillance of distant metastases, Feliu et al. implemented a mouse model in which a mouse colorectal tumor cell line was grafted into both the colon and liver. They found that the presence of an intracolon tumor evoked rejection of an intrahepatic tumor in these mice compared with mice bearing solely intrahepatic tumors. Immunoprofiling and cell-tracking experiments revealed that α4β7 integrin–expressing enterotropic CD8⁺ T cells that recognize tumor antigens trafficked from gut-draining lymph nodes of mice with intracolon tumors and accumulated in hepatic tumors. Treatment of mice with α4β7 integrin–depleting antibodies reversed this antimetastatic phenotype, implicating enterotropic α4β7-expressing CD8⁺ T cells as key mediators of systemic cancer immunosurveillance. An intracolon tumor also favorably influenced immune responses in hepatic tumors after ICB treatment in mice.

Feliu et al. analyzed samples from 20 patients with microsatellite stable metastatic colorectal cancer and found that the frequency of patients with metastatic tumors expressing integrin β7 (ITGB7) and integrin α4 (ITGA4) genes was higher among ICB responders than in nonresponders. Moreover, in this same patient cohort, the authors found higher concentrations of circulating α4β7 integrin–expressing CD8⁺ T cells in blood from ICB responders than in blood from nonresponders. Together, these data support a critical role for enterotropic α4β7-expressing CD8⁺ T cells in systemic cancer immunosurveillance and their potential utility as predictive biomarkers of ICB responsiveness in patients with metastatic colorectal cancer.

The studies of Fidelle et al. and Feliu et al. highlight disparate roles for α4β7 integrin–expressing cytotoxic CD8⁺ T cells and immunosuppressive CD4⁺ T_reg17 cells in systemic cancer immunosurveillance (see the figure). Although Fidelle et al. show that metabolites produced by Enterocloster species may repress endothelial MAdCAM-1 expression in the gut, it remains to be determined what signals control the composition and degree to which protumorigenic enterotropic T_reg17 cells, antitumorigenic enterotropic CD8⁺ T cells, and other enterotropic lymphocyte populations are mobilized from the gut to distant tumor sites. In addition to T_reg17 cells, Fidelle et al. demonstrate that antibiotic treatment induces an exodus of multiple subsets of enterotropic CD4⁺ and CD8⁺ T cells; however, enterotropic CD8⁺ T cells that reached distant sarcomas exhibited features of exhaustion. Feliu et al. show that robust antimetastatic responses by enterotropic CD8⁺ T cells were dependent on a vigorous antitumor immune response to the intracolon tumor, but the exact mechanisms that triggered the exodus of cytotoxic enterotropic T cells from the gut and the accompanying abscopal effect (whereby immune responses to one tumor can reject other related tumors) require further investigation. Uncovering the cues that control the kinetics and magnitude of enterotropic T cell trafficking may reveal new immunotherapy modalities or combinatorial strategies to boost existing approaches.

Enterotropic T cells modulate responses to cancer immunotherapy in mice.

Naïve T cells activated in the gut-draining lymph nodes differentiate into specialized T cell subsets that express the α4β7 integrin, which engages the mucosal addressin cell adhesion molecule 1 (MAdCAM-1) ligand that is expressed on intestinal endothelial cells. These enterotropic T cells can influence systemic antitumor immunity and responses to immunotherapy.

The work by Feliu et al. may also inspire new avenues for improving adoptive T cell therapies (whereby patient T cells are engineered to target tumors) through appropriation of attributes that confer potent antitumor activity to α4β7 integrin–expressing CD8⁺ T cells. Indeed, they demonstrate that α4β7 integrin–expressing CD8⁺ T cells may have a superior capacity for cytotoxic activity compared with CD8⁺ T cells that lack α4β7 integrin. Deeper molecular profiling of gut-emigrating protumorigenic and anti-tumorigenic enterotropic T cell populations may further unveil key functional attributes of these cells, their relationship with other T cell subsets, and the drivers of their identity and trafficking behavior.