Immunity, immunotherapy, and rectal cancer: A clinical and translational science review

Abstract

Rectal cancer remains a challenging disease to treat. Therapy for locally advanced rectal cancer (LARC), the most frequent presentation, has evolved to include a multimodal approach of radiation, chemotherapy, and surgery. While this approach improves local disease control, the distant recurrence rate is nearly 30% and treatment-related morbidity is substantial, thus underscoring the need for new therapeutic approaches with better efficacy and lower side effects. Immunotherapy could potentially fill this need, but its promise is not yet realized in rectal cancer. In this translational science review, we address what is known about how cytotoxic therapies shape rectal cancer immunity and potentially prime the tumor microenvironment for response to immune checkpoint inhibitors and other immunotherapies. We also address the role of current immunotherapies in colorectal cancer and highlight where novel immunotherapy approaches are currently being evaluated in LARC. Finally, we address important future directions in LARC immunotherapy including the need to define optimal therapeutic sequencing, predictive biomarkers, strategies to limit treatment-related side effects and the potential of gut microbiome manipulation to improve outcomes. In summary, this review provides a framework to guide future research and inform immunotherapy trial design so as to advance rectal cancer care.

Figure 1.. Impact of Radiation and Chemotherapy on the tumor microenvironment.

Illustration of how both modalities have the ability stimulate and/or suppress immunity as related to rectal cancer. 5-FU, F-fluorouracil; APC, antigen-presenting cell; CTL, cytotoxic T lymphocytes; CTLA-4, cytotoxic T-lymphocyte-associated protein 4; DAMP, damage-associated molecular patterns; FOLFOX, 5-FU/Leucovorin/Oxaliplatin; IDO1, indoleamine 2,3, dioxygenase 1; IFN-γ, interferon gamma; MHC-I, Major Histocompatabillity Complex I; MDSC, myeloid-derived suppressor cells; NK, natural killer cells; PD-1, Programmed Death 1; PD-L1, Programmed Death Ligand 1; TAM, tumor-associated macrophages; TGF-β, tumor growth factor-beta; TLR, toll-like receptors; TME, Tumor Mircoenvironment; Tregs, regulatory T cell; Type I IFN, Type I Interferon

Figure 2.. Current and potential cellular targets for immunotherapy in rectal cancer.

CD40-L, CD40 Ligand; CTLA-4, cytotoxic T lymphocyte-associated protein 4; HSV, herpes simplex virus; IDO1, indoleamine 2,3, dioxygenase 1; MHC-I, major histocompatibility complex I; PD-1, programmed death 1; PD-L1, programmed death ligand 1; TCR, T cell receptor; TGF-β, transforming growth factor beta