T Cells Dominate the Local Immune Response Induced by Intralesional IL-2 in Combination with Imiquimod and Retinoid for In-Transit Metastatic Melanoma

Abstract

is an RNase essential for controlling immune responses by regulating mRNA decay. Nature 2009;458(7242):1185e90. Milora KA, Fu H, Dubaz O, Jensen LE. Unprocessed interleukin-36a regulates psoriasis-like skin inflammation in cooperation with interleukin-1.

Insights into the Molecular Mechanisms Behind Intralesional Immunotherapies for Advanced Melanoma

“…Thus, systemic toxicity is blunted; it seems to be limited to the effects of the cytokine response associated with the anti-tumor immune response, and not to a systemic activation of autoimmune T cells. Importantly, some evidence suggests that intralesional approaches may be able to induce potent systemic anti-tumor immune responses [16,[22][23][24]29,41,48,57,107], likely due to tumor antigen-primed cytotoxic T cells that home towards the chemokine storm induced by the host-tumor immune reaction.…”

“…Indeed, further retrospective case studies of 11 patients treated with high-dose intralesional IL2, imiquimod, and retinoid cream also showed a 100% CR with relatively minor toxicities [33]. In further mechanistic studies, lesions treated with the combination therapy had significantly increased expression of a myriad of pro-inflammatory Th1-like cytokines, notably: IFNγ, IL6, TNF, and IL2Rα [57]. Additionally, expression of Th1-promoting transcription factors T-bet, STAT4, and STAT1 were significantly increased, while both Th2-promoting transcription factor GATA3 and Th17-promoting transcription factor RORC were significantly decreased [57].…”

“…In further mechanistic studies, lesions treated with the combination therapy had significantly increased expression of a myriad of pro-inflammatory Th1-like cytokines, notably: IFNγ, IL6, TNF, and IL2Rα [57]. Additionally, expression of Th1-promoting transcription factors T-bet, STAT4, and STAT1 were significantly increased, while both Th2-promoting transcription factor GATA3 and Th17-promoting transcription factor RORC were significantly decreased [57]. Akin to the findings reported with intralesional IL2 and imiquimod alone [56], the peripheral CD4 + /CD8 + T cell ratio was significantly increased, with a specific expansion of both activated T lymphocytes and memory T cell populations [57].…”

“…Additionally, expression of Th1-promoting transcription factors T-bet, STAT4, and STAT1 were significantly increased, while both Th2-promoting transcription factor GATA3 and Th17-promoting transcription factor RORC were significantly decreased [57]. Akin to the findings reported with intralesional IL2 and imiquimod alone [56], the peripheral CD4 + /CD8 + T cell ratio was significantly increased, with a specific expansion of both activated T lymphocytes and memory T cell populations [57]. These findings, together with the observation that all of the patients suffered some vitiligo (an immune-mediated attack on melanocytes [84]), support the notion of a systemic immune response against aberrant melanocyte antigens.…”

“…Addition of retinoid signaling further increases anti-tumor Th1 cytokines IL6, TNFα, and IL2Rα. Th1 transcription factors T-bet, STAT1, and STAT4 are increased, while Th2 and Th17 transcription factors GATA3 and RORC are decreased[57].• Anti-melanocyte immune response (vitiligo) is noted, with presence of immune effector T cells and memory T cells in the infiltrate[57].…”