Friday, September 4, 2015

NSAIDs show synergy with anti-PD1 antibody in cancer immunotherapy

Tumor progression from a single cell to a multicellular state can take years and several mutations that allow cancer cells to (1) expand uncontrollably, and (2) adopt natural defense mechanisms against immune surveillance (commonly referred as tolerance). 

Ordinarily, healthy (or healing) tissues defend themselves against excessive immune probing by secreting or expressing inhibitory molecules. Each healthy tissue will have its own suitable natural defense(s) against excessive immune probing.

There are several known tissue specific inhibitory signals. Many are still unknown. By understanding how healthy tissues communicate tolerogenic signals to immune system we can gain better control over cancer tissue (because cancer tissues are imitating the same tolerogenic state). 

For example, new pepar in prestigious journal Cell showed that blockade of COX1/COX2 enzymes leads to tumor control by adaptive immune system. COX1/COX2 enzymes are the same enzymes the drugs such as aspirin targets to relieve the pain. 

This is very straightforward article. The reason it is in Cell has to due with CRISPR/Cas9 technology the authors has used to develop COX1 or COX1/COX2 double deficient tumor cell lines. The senior author on this paper is Caetano Reis e Sousa, a wellknown name among immunologists. This study was done at the Francis Crick Institute in London which  will be the largest biomedical institution in Europe when completed.

Initially, the authors developed melanoma-prone cell lines (Brafv600E) deficient for COX enzymes using CRISPR/Cas9 technology.

Next, the authors showed that Brafv600E melanoma tumor cells deficient for COX1/2 enzymes lack the ability to secrete PGE2 (among other bioactive lipids), a prostaglandin molecule known for its immunomodulating property.

The authors observed that when transplanted COX1/2 DKO melanoma Brafv600E tumor cells (but not parental cells) were rejected by wild-type, but not by RAG KO hosts, implying the role of adaptive immune system in recognizing tumor cells in absence of PGE2.

Similar results were obtained with melanoma Brafv600E tumor cells selectively deficient for PGE2 synthase.

Growth of other tumor cell lines (colorectal and breast cancer cells) deficient for COX1/2 enzymes were also controlled by adaptive immune system in wild-type hosts, though less efficiently compared to melanoma cells (the authors do not indicate whether these tumors were ultimately rejected or stayed dormant).

Finally, the authors showed that combination of aspirin (that blocks COX1/2 enzymes) and anti-PD1 antibody could synergize in inhibiting tumor growth (here also it is not clear what term "rejection" means, since tumor growth graph and rejection graph are not identical).

In summary, the data presented in this paper expands our understanding of "natural" defenses of tumor cells against immune probing. Here, tumor growth was controlled by T cells and it could generate memory response to secondary tumor transplantation.

One weakness of this study is the tumor transplantation model itself. The authors did not study already established tumors but rather than they followed the tumor growth or implemented therapy immediately after transplantation. This approach seems to lack a clinical relevance for human cancers where patients are frequently first seen with already established tumors (sometimes quite in advance stages).

David Usharauli

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