Immune approaches beyond traditional immune checkpoint inhibitors for advanced renal cell carcinoma.

Renal cell carcinoma (RCC), especially clear cell RCC, is generally considered an immunotherapy-responsive cancer. Recently, the prognosis for patients with locally advanced and metastatic RCC has significantly improved with the regulatory approvals of anti-PD-1/PD-L1/CTLA-4 immune checkpoint inhibitor (ICI)-based regimens. Yet in most cases, RCC will remain initially unresponsive to treatment or will develop resistance over time. Hence, there remains an unmet need to understand what leads to ICI resistance and to develop novel immune and nonimmune treatments to enhance the response to ICIs. In this review, we highlight recently published studies and the latest clinical studies investigating the next generation of immune approaches to locally advanced and metastatic RCC beyond traditional ICIs. These trials include cytokines, gut microbiota-based therapies, novel immune checkpoint agents, vaccines, and chimeric antigen receptor T cells. These agents are being evaluated as monotherapy or in combination with traditional ICIs and will hopefully provide improved outcomes to patients with RCC soon.

Immune checkpoint blockade induces gut microbiota translocation that augments extraintestinal antitumor immunity.

Gut microbiota, specifically gut bacteria, are critical for effective immune checkpoint blockade therapy (ICT) for cancer. The mechanisms by which gut microbiota augment extraintestinal anticancer immune responses, however, are largely unknown. Here, we find that ICT induces the translocation of specific endogenous gut bacteria into secondary lymphoid organs and subcutaneous melanoma tumors. Mechanistically, ICT induces lymph node remodeling and dendritic cell (DC) activation, which facilitates the translocation of a selective subset of gut bacteria to extraintestinal tissues to promote optimal antitumor T cell responses in both the tumor-draining lymph nodes (TDLNs) and the primary tumor. Antibiotic treatment results in decreased gut microbiota translocation into mesenteric lymph nodes (MLNs) and TDLNs, diminished DC and effector CD8+ T cell responses, and attenuated responses to ICT. Our findings illuminate a key mechanism by which gut microbiota promote extraintestinal anticancer immunity.

Mast Cells: A New Frontier for Cancer Immunotherapy.

Mast cells are unique tissue-resident immune cells of the myeloid lineage that have long been implicated in the pathogenesis of allergic and autoimmune disorders. More recently, mast cells have been recognized as key orchestrators of anti-tumor immunity, modulators of the cancer stroma, and have also been implicated in cancer cell intrinsic properties. As such, mast cells are an underrecognized but very promising target for cancer immunotherapy. In this review, we discuss the role of mast cells in shaping cancer and its microenvironment, the interaction between mast cells and cancer therapies, and strategies to target mast cells to improve cancer outcomes. Specifically, we address (1) decreasing cell numbers through c-KIT inhibition, (2) modulating mast cell activation and phenotype (through mast cell stabilizers, FcεR1 signaling pathway activators/inhibitors, antibodies targeting inhibitory receptors and ligands, toll like receptor agonists), and (3) altering secreted mast cell mediators and their downstream effects. Finally, we discuss the importance of translational research using patient samples to advance the field of mast cell targeting to optimally improve patient outcomes. As we aim to expand the successes of existing cancer immunotherapies, focused clinical and translational studies targeting mast cells in different cancer contexts are now warranted.