Sunday, September 13, 2015

Tumor cell-intrinsic effects of α-PD1 therapy in absence of adaptive immune system

α-PD1 antibody immunotherapy shows significant benefits in cancer patients. In some settings, α-PD1 immunotherapy is even superior to α-CTLA4 immunotherapy. Since both α-PD1 and α-CTLA4 immunotherapy work as the immune checkpoint inhibitors, question then is what determines such selective advantage of α-PD1 immunotherapy?  

New paper in journal Cell may provide the clue. Here, the authors reported that α-PD1 antibody could delay cancer cell growth independent of its role on adaptive immune system.

First, using several complementary approaches (Flow Cytometry, RT-PCR, In Situ staining), the authors confirmed that melanoma cells (both primary and cell lines in both human and mouse) expressed PD1.

Next, using mouse melanoma transplantation model, the authors showed that melanoma growth correlated with the level of PD1 expression (wherein PD1high tumors grow faster [PD1 over-expression (OE)], and PD1low tumors grow slower [PD1 shRNA]) and this effect was independent of adaptive immune system (NSG mice, see below).

Using anti-PDL1 antibody blockade, the authors showed that tumor growth promoting effect of PD1 over-expression (OE) was PD-1 specific (and not off-target effect).

Similar, cancer cell-intrinsic effect of PD1 signaling were seen with human melanoma cells transplanted in NSG mice (NSG mouse lack adaptive immune system and has minimal NK cell activity).

To verify cancer cell-intrinsic effect of PD1 in unmodified cells, the authors transplanted mouse parental melanoma cells (B16-F10) into wild-type, PD1 KO or NSG mice. Here, α-PD1 antibody therapy could delay tumor growth in PD1 KO and NSG mice, but strangely not in wild-type mice (this goes against human clinical trials).

However, more importantly, α-PD1 antibody therapy could delay patient-derived melanoma cell growth in NSG mice (it appears that human melanoma cells are more sensitive to α-PD1 therapy compared to mouse melanoma cells).

In summary, these results suggest that some portion of anti-tumor effect seen with α-PD1 antibody therapy could be attributed to the cancer cell-intrinsic effects of PD1 signaling, independent of its role on adaptive or innate immune system (i.e. independent of its role as a checkpoint inhibitor).

David Usharauli 

No comments:

Post a Comment