Interleukin-2 signals converge in a lymphoid–dendritic cell pathway that promotes anticancer immunity

Abstract

Tumor-infiltrating dendritic cells (DCs) correlate with effective anticancer immunity and improved responsiveness to anti–PD-1 checkpoint immunotherapy. However, the drivers of DC expansion and intratumoral accumulation are ill-defined. We found that interleukin-2 (IL-2) stimulated DC formation through innate and adaptive lymphoid cells in mice and humans, and this increase in DCs improved anticancer immunity. Administration of IL-2 to humans within a clinical trial and of IL-2 receptor (IL-2R)–biased IL-2 to mice resulted in pronounced expansion of type 1 DCs, including migratory and cross-presenting subsets, and type 2 DCs, although neither DC precursors nor mature DCs had functional IL-2Rs. In mechanistic studies, IL-2 signals stimulated innate lymphoid cells, natural killer cells, and T cells to synthesize the cytokines FLT3L, CSF-2, and TNF. These cytokines redundantly caused DC expansion and activation, which resulted in improved antigen processing and correlated with favorable anticancer responses in mice and patients. Thus, IL-2 immunotherapy–mediated stimulation of DCs contributes to anticancer immunity by rendering tumors more immunogenic.

CD122-directed interleukin-2 treatment mechanisms in bladder cancer differ from αPD-L1 and include tissue-selective γδ T cell activation

“…A Tγδ17-MDSC immunosuppressive axis had been previously identified in human colorectal carcinoma, 43 which could be disrupted by IL-2c treatment based on our data. Further, RAG1 KO mice have functional innate lymphoid cells that contributed to IL-2c efficacy against subcutaneous B16 melanoma challenge, 12 whereas IL-2c did not treat subcutaneous MB49 in these studies, further supporting tissue- and/or tumor-specific IL-2c effects requiring additional investigations.…”

“… 43 Interestingly, we found that IL-2c reduced the frequency ( figure 6D ) and number ( figure 6E ) of bladder TNF-α + Vγ4δ4 cells, with a concomitant reduction in PMN-MDSC frequency ( figure 6F ). Intratumoral monocytic MDSC (M-MDSC) content was unchanged by IL-2c ( online supplemental figure S4E ), suggesting that IL-2c treatment could include a specific reduction of PMN-MDSCs, possibly via IL-17 or TNF-α effects that could include IL-2c-induced TNF-α production by innate lymphoid cells recently described in a subcutaneous melanoma model, 12 an area requiring further investigation.…”

“… 53 We found that IL-2c reduced orthotopic PMN-MDSC frequency, which could be from an IL-17/TNF-α signaling effect based on prior reports, 43 and could specifically include TNF-α from innate lymphoid cells, a novel IL-2c effect just reported. 12 MDSC-mediated immunosuppression of BC immunotherapy responses merit additional investigation and may be linked to other beneficial IL-2c effects. A Tγδ17-MDSC immunosuppressive axis had been previously identified in human colorectal carcinoma, 43 which could be disrupted by IL-2c treatment based on our data.…”

“… 9 10 CD122-directed IL-2 therapy using distinct molecules is also promising in human BC trials, including when combined with αPD-1. 11 Effects on other CD25 + and CD122 + cells including γδ T cells using targeted IL-2 therapies are unreported to our knowledge and recent reports suggest IL-2c can also act through non-IL-2 receptor expressing cells such as dendritic cells, 12 necessitating improved understanding of specific treatment mechanisms in distinct tumor microenvironments.…”

Skin immunization for effective treatment of multifocal melanoma refractory to PD1 blockade and Braf inhibitors

“…Furthermore, accumulated evidence suggests that IL2 signaling in the TME favors responsiveness to PD1 blockade. [70][71][72][73] As shown in figure 7H,I, skin immunization resulted in the recruitment of increased levels of IL2 + CD4 + TIL in the tumor core, which may at least partially explain the ability of skin immunization to convert PD1-resistant tumors into αPD1responsive tumors (figures 2A and 4D).…”