It is now well accepted that similar to cytotoxic CD8 T cells, antigen-specific effector CD4 T cells can show a direct anti-tumor effect both in mice and humans. This concept is still relatively new (actually first paper about it was published only in 2003). Incorporation of CD4 T cells and MHC II + peptides in tumor immunotherapy strategy increases chances of finding tumor-specific antigens (epitopes) relevant for personalized cancer medicine.
In this regard, new paper from journal Immunity is of interest. There, the authors showed that unlike CD8 T cells, intra-clonal competition of adoptive transfer CD4 T cells [at high precursor frequency] improved rather than diminished its anti-tumor effect and productive effector differentiation.
In this study, the authors transferred different number (103, 104, 105, 106) of melanoma antigen, TRP-1 specific CD4 T cells into mice implanted with melanoma. Despite significant expansion at low precursor frequency, only high frequency transferred TRP-1 specific CD4 T cells managed to control and eradicate established tumors.
Moreover, the authors showed that in this settings, only TRP-1 specific CD4 T cells from high frequency adoptive transfer hosts underwent productive effector differentiation.
Even addition of anti-PD1 antibody to [low frequency] TRP-1 specific CD4 T cell adoptive transfer hosts failed to rescue their differentiation (increase in IL-21 is a marker of CD4 T cell exhaustion).
In summary, this study suggests that for CD4 T cells intra-clonal competition does not prevent efficient effector differentiation and establishment of productive anti-tumor immunity. It appears that CD4 T cells undergoing significant expansion at low precursor frequency develop "early and checkpoint inhibition-refractory exhaustion" preventing them to participate in effective anti-tumor response. This knowledge should be taken into account when considering adoptive T cell tumor therapy and checkpoint inhibition (according this study, anti-PD1 therapy could potentially accelerate tumor-specific CD4 T cell exhaustion at low precursor frequency).
David Usharauli
Moreover, the authors showed that in this settings, only TRP-1 specific CD4 T cells from high frequency adoptive transfer hosts underwent productive effector differentiation.
Even addition of anti-PD1 antibody to [low frequency] TRP-1 specific CD4 T cell adoptive transfer hosts failed to rescue their differentiation (increase in IL-21 is a marker of CD4 T cell exhaustion).
In summary, this study suggests that for CD4 T cells intra-clonal competition does not prevent efficient effector differentiation and establishment of productive anti-tumor immunity. It appears that CD4 T cells undergoing significant expansion at low precursor frequency develop "early and checkpoint inhibition-refractory exhaustion" preventing them to participate in effective anti-tumor response. This knowledge should be taken into account when considering adoptive T cell tumor therapy and checkpoint inhibition (according this study, anti-PD1 therapy could potentially accelerate tumor-specific CD4 T cell exhaustion at low precursor frequency).
David Usharauli
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