This week Science Translational Medicine published 2 papers directly or indirectly related to Foxp3+ T cells [this is in in addition of two Foxp3+ T cell papers in Nature]. Since I am very curious about the role of Foxp3+ T cells in immune regulation I decided to review them.
First paper I review here is not a typical Foxp3+ T cell paper. It is actually a study of tumor immunotherapy. The authors showed that when combined with checkpoint inhibitors CTLA-4/PD-1, direct tumor immunotoxins, such as T-DM1 [trastuzumab emtansine], significantly augment anti-cancer immune response and immune memory.
Trastuzumab [herceptin] is a humanized antibody that targets HER2 antigen over-expressed in breast cancer cells. Initially, the authors showed that anti-cancer effect of ado-trastuzumab conjugated to cancer toxin, T-DM1 (Kadcyla®), was depended on T cells [as revealed by T cell depletion]. This suggested potential synergy with checkpoint inhibitors.
Indeed, a combined application of T-DM1 and CTLA-4/PD-1 antibodies showed close to 100% protection against breast cancer in mice.
Surprisingly, the authors noticed that combo therapy, that fully protected mice against tumors, actually increased infiltration of tumor tissue by functioning Foxp3+ T cells [in addition to conventional T cells]. This was counter-intuitive.
However, T cell depletion confirmed that when CD4 T cells [that includes Foxp3+ T cells] were removed, more than 50% of mice on combo therapy [100% tumor-free] developed severe autoimmune inflammation [results with Treg-specific depletion would have been more valuable here, of course].
In summary, this study points to 2 distinct results: first, direct cancer cytotoxocity by immunotoxins could synergize with checkpoint inhibitors, probably via efficient antigen uptake and DC maturation [antigen processing stage]. Second, tumor infiltrating Foxp3+ T cell could play not yet understood tissue protective role during such combo immunotherapy [in effector stage].
David Usharauli
First paper I review here is not a typical Foxp3+ T cell paper. It is actually a study of tumor immunotherapy. The authors showed that when combined with checkpoint inhibitors CTLA-4/PD-1, direct tumor immunotoxins, such as T-DM1 [trastuzumab emtansine], significantly augment anti-cancer immune response and immune memory.
Trastuzumab [herceptin] is a humanized antibody that targets HER2 antigen over-expressed in breast cancer cells. Initially, the authors showed that anti-cancer effect of ado-trastuzumab conjugated to cancer toxin, T-DM1 (Kadcyla®), was depended on T cells [as revealed by T cell depletion]. This suggested potential synergy with checkpoint inhibitors.
Indeed, a combined application of T-DM1 and CTLA-4/PD-1 antibodies showed close to 100% protection against breast cancer in mice.
Surprisingly, the authors noticed that combo therapy, that fully protected mice against tumors, actually increased infiltration of tumor tissue by functioning Foxp3+ T cells [in addition to conventional T cells]. This was counter-intuitive.
However, T cell depletion confirmed that when CD4 T cells [that includes Foxp3+ T cells] were removed, more than 50% of mice on combo therapy [100% tumor-free] developed severe autoimmune inflammation [results with Treg-specific depletion would have been more valuable here, of course].
In summary, this study points to 2 distinct results: first, direct cancer cytotoxocity by immunotoxins could synergize with checkpoint inhibitors, probably via efficient antigen uptake and DC maturation [antigen processing stage]. Second, tumor infiltrating Foxp3+ T cell could play not yet understood tissue protective role during such combo immunotherapy [in effector stage].
David Usharauli
