Requirement for Innate Immunity and CD90+ NK1.1− Lymphocytes to Treat Established Melanoma with Chemo-Immunotherapy

Abstract

We sought to define cellular immune mechanisms of synergy between tumor-antigen–targeted monoclonal antibodies and chemotherapy. Established B16 melanoma in mice was treated with cytotoxic doses of cyclophosphamide in combination with an antibody targeting tyrosinase-related protein 1 (αTRP1), a native melanoma differentiation antigen. We find that Fcγ receptors are required for efficacy, showing that antitumor activity of combination therapy is immune mediated. Rag1−/− mice deficient in adaptive immunity are able to clear tumors, and thus innate immunity is sufficient for efficacy. Furthermore, previously treated wild-type mice are not significantly protected against tumor reinduction, as compared with mice inoculated with irradiated B16 alone, consistent with a primarily innate immune mechanism of action of chemo-immunotherapy. In contrast, mice deficient in both classical natural killer (NK) lymphocytes and nonclassical innate lymphocytes (ILC) due to deletion of the IL2 receptor common gamma chain IL2γc−/−) are refractory to chemo-immunotherapy. Classical NK lymphocytes are not critical for treatment, as depletion of NK1.1+ cells does not impair antitumor effect. Depletion of CD90+NK1.1− lymphocytes, however, both diminishes therapeutic benefit and decreases accumulation of macrophages within the tumor. Tumor clearance during combination chemo-immunotherapy with monoclonal antibodies against native antigen is mediated by the innate immune system. We highlight a novel potential role for CD90+NK1.1− ILCs in chemo-immunotherapy.

Effects of Combined Treatment with Branched-Chain Amino Acids, Citric Acid, L-Carnitine, Coenzyme Q10, Zinc, and Various Vitamins in Tumor-Bearing Mice

“…Some studies set the endpoint as the time when the melanoma reached a certain size. 13,14) Others set the endpoint as a certain day (from day 6 to 28) after melanoma cells were implanted, though the basis for selecting the day was not provided. [15][16][17][18] In the beginning of our study, we considered measuring the tumor volume over time, but opted not to do so because of the inaccuracy due to the irregular shape of the tumor formed by the melanoma cells used in the study.…”

Ambiguous roles and potential therapeutic strategies of innate lymphoid cells in different types of tumor (Review)

“…Furthermore, Lotfi et al (68) and Ikutani et al (69) reported that ILC2s had increased expression levels of IL-5 in tumor tissue that resulted in the recruitment and activation of eosinophils, which was linked to an improved prognosis in numerous types of solid tumor. More recently, a subset of NK1.1-negative ILCs was reported to be responsible for the impact of a combined chemotherapy and immunotherapy treatment regimen in a murine B16 melanoma model, highlighting the potential anti-tumor role for ILC2s and/or ILC3s (70). Conversely, in certain cases, LTi-cell recruitment in melanoma was reported to be correlated with the expression of CCL21 in the tumor, which was discovered to be a signal to transform the tumor microenvironment from immunogenic to tolerogenic, which subsequently promoted immune evasion (71).…”

Ambiguous roles of innate lymphoid cells in chronic development of liver diseases

“…The protective role of ILC3s has been directly revealed for its contribution to the formation of protective tumor-associated tertiary lymphoid structures in non-small cell lung cancer (NSCLC)[ 134 ]. The ILC3s are able to up-regulate adhesion molecules in the tumor microenvironment to enhance leukocyte invasion, and have been characterized as important mediators of the efficacy of a combination therapy of chemotherapy and tumor antigen-targeted monoclonal antibodies[ 135 ]. Though there is no direct evidence linking ILC3s and liver cancer, the connection can be inferred according to their role in colorectal cancer, as well as the ambiguous roles of their downstream effector cytokines, including IL-22 and IL-17.…”