CTLA‐4 inhibition facilitates follicular T and B cell interaction and the production of tumor‐specific antibodies

Immune checkpoint inhibitors (ICIs) induce activation and expansion of cytotoxic T cells. To depict a comprehensive immune cell landscape reshaped by the CTLA‐4 checkpoint inhibitor, we performed single‐cell RNA sequencing in a mouse syngeneic tumor transplant model. After CTLA‐4 inhibition, tumor regression was accompanied by massive immune cell expansion, especially in T and B cells. We found that B cells in tumor transplant represented follicular, germinal center and plasma B cells, some of which shared identical B cell receptor clonotypes and possessed tumor reactivity. Furthermore, the posttreatment tumor contained a tertiary lymphoid‐like structure with intermingled T and B cells. These data suggest germinal center formation within the tumor mass and in situ differentiation of tumor‐specific plasma cells. Taken together, our data provide a panoramic view of the immune microenvironment after CTLA‐4 inhibition and suggest a role for tumor‐specific B cells in antitumor immunity. What's new? Combined inhibition of the immune checkpoint molecule CTLA4 and the co‐inhibitory immune factor PD‐1 increases T‐cell activation, leading to tumor regression. In addition to T cells, CTLA4 and PD‐1 inhibitors influence other immune cells, though these effects remain understudied. Here, using single‐cell RNA sequencing, the authors show that CTLA4 inhibition induces differentiation of naïve B cells into antibody‐producing plasma cells within tumor transplants in mice. Based on clonal B‐cell receptor sequences, recombinant antibodies were produced and validated for tumor reactivity. The findings indicate that in situ B cell activation occurs in human cancers, opening a path to new therapeutic strategies.