While a high frequency of Th1 cells in tumors is associated with improved cancer prognosis, this benefit has been attributed mainly to support of cytotoxic activity of CD8+ T cells. By attempting to potentiate antibody-driven immunity, we found a remarkable synergy between CD4+ T cells and tumor-binding antibodies. This surprising synergy was mediated by a small subset of tumor-infiltrating CD4+ T cells that express the high-affinity Fcγ receptor for IgG (FcγRI) in both mouse and human patients. These cells efficiently lyse tumor cells coated with antibodies through concomitant crosslinking of their T cell receptor (TCR) and FcγRI. By expressing FcγRI and its signaling chain in conventional CD4+ T cells, we successfully employed this mechanism to treat established solid cancers. Overall, this discovery sheds new light on the biology of this T cell subset, their function during tumor immunity, and the means to utilize their unique killing signals in immunotherapy.
Diana Rasoulouniriana, Nadine Santana-Magal, Amit Gutwillig, Leen Farhat-Younis, Yariv Wine, Corey Saperia, Lior Tal, Haim Gutman, Alexander Tsivian, Ronen Brenner, Eiman Abu Bandora, Nathan E. Reticker-Flynn, Peleg Rider, Yaron Carmi
Submitter: Anil Chauhan | email@example.com
Authors: Anil Chauhan
Saint Louis University
Published July 10, 2020
The recently published article by Rasoulouniriana et. al, demonstrate that the FcgR1 expressing CD4+ Th1 subset exert antibody-mediated cytotoxic activity, report an important FcR mediated function. (1). The role of Fc receptors (FcRs) in CD4+ T cell function remains controversial (2-4). Authors suggested that the Th1 population only express FcgRI, though their flow analysis also show FcgRII/FcgRIII (Fig. 3A). Indeed, Th1 population can be generated from ICs ligation to CD16a on human naïve CD4+ T cells (5). It would have been nice to identify, which of three FcR+ populations produce IFN-g. There is no existing experimental data that support the absence of FcR expression from CD4+ T cells (3). Many groups, including ours have established the existence of FcRs on activated CD4+ T cells (2, 4, 5). FcR signaling drives the differentiation of human naïve CD4+ T cells into IFN-g producing T-bet+ Th1 cells (5-7). However, as implied in the article, we did not show that IFN-g exposure triggered FcR expression or cellular activation. FcgRIIIa activation by ICs is required for type I and II IFN expression (7). Signaling from FcgRIIa and FcmR1 also trigger IFN-g production (9, 10). We disagree that the Th1 cells observed are exhausted. The levels of expression of TIM3, LAG3, and PD1 stained in FcgRI+ cells upon PMA + Ionomycin is not convincing and these markers should have been examined in anti-CD3 +anti-CD28 treated cells. Authors showed Syk, which would suggest an activated state, and to make a case for exhausted state, should have performed co-staining. The FcgRIIa and FcgRIIIa signaling shows pSyk in cells, which express CD25, CD69, and CD98, suggesting cellular activation (7, 11).
Requirement of TRP-1 and anti-TRP-I to kill tumor cells, suggests type II hypercreativity reaction. Authors suggested that combined TRP1-reactive TCR, FcgRI, and FcRg T cells and anti-TRP1 antibodies induced tumor eradication. FcRs that bind to ICs are present on the activated CD4+ T cell membranes with CD3 complex in clustered membrane rafts (12).
The authors suggested that IFN-g triggered lysosome production that resulted in cell death. FcR signaling upregulates the granzymes. We observed enhanced expression of Gran A from FcR signaling. Forced expression of FcRg enhances the ADCC and CD16a expression (13, 14). The modest PD1+ population produces IFN-g (6). We are of the opinion that the FcR expressing cells do not represent exhausted cells as suggested in this study. Other interpretation of their result is also possible.
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