T CELLS promote the growth of small-cell lung carcinoma via an IL-6/CD74 axis

A central challenge in immuno-oncology is overcoming the limited efficacy and durability of immune checkpoint inhibition (ICI). This is particularly true in small-cell lung cancer (SCLC), where chemotherapy plus ICI is standard of care but rarely curative. Here, we found that T cells are surprisingly both necessary and sufficient for optimal tumor growth in mouse models of SCLC. These pro-tumoral effects are mediated by interleukin-6 (IL-6) production, which induces the pro-survival factor CD74 in SCLC cells. Notably, T cells within human SCLC tumors express IL-6, and low IL-6 signaling correlates with improved survival following chemotherapy plus ICI in patients. Accordingly, IL-6 blockade synergizes with ICI to inhibit SCLC growth in vivo. These findings reveal a paradoxical role for T cells in SCLC, uncovering an unexpected T cell-IL-6-CD74 axis that promotes tumor survival, and identify IL-6 as a promising target to help unleash the full potential of immunotherapy in this aggressive cancer.