Anti-PD1 immunotherapy facilitates antitumor immune response and is shown to increase survival of melanoma patients. However, response rates are low and not always predictable.  Molecular markers that predict response to therapy may direct therapeutic regimens. 
The unfolded protein response (UPR) protects the cell from apoptosis augmented by misfolded or unfolded proteins. Activation of the UPR has been reported to promote tumorigenesis and to alter immune response in different types of cancer. Glucose regulatory protein 78 (GRP78) is the master regulator of the UPR. The aim of this retrospective study was to determine the role of GRP78 in response to anti-PD1 immunotherapy in melanoma patients. Biopsy samples from 20 melanoma patients who received anti-PD1 immunotherapy as first line monotherapy, were stained using immunohistochemistry for GRP78 level. The expression of GRP78 in cancer cells was quantified, and compared to response, according to Response Evaluation Criteria in Solid Tumors (RECIST). 
We found that low GRP78 level correlated with good response to immunotherapy, whereas high GRP78 levels were found only in non- responders (p<0.05). Accordingly, low GRP78 levels correlated with significantly higher progression free and over-all survival. These results suggest that GRP78 may serve as a marker to stratify patients for anti PD1 immunotherapy. Validation of these findings in a larger cohort of patients, as well as in the context of additional immunotherapies is needed.

Low GRP78 protein level predicts response to PD1 therapy and good prognosis in melanoma