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Jonathan Samaniego

BIOL 547

TGF Beta attenuates tumor response to PD-L1 blockade by contributing to exclusion of T-cells
Paper summary

In efforts to improve cancer treatment and outcomes, studies have been done to show the effect of
blocking the programmed death ligand 1 (PD-L1) pathway. PD-L1 is a protein that has been shown to
suppress the human immune system by inhibiting T cell proliferation and activation. T- cells play a
major role in identifying and mounting an immune response on cancer cells. Hence, blocking PD-L1
pathway could mean a positive response in certain cancers. However, a response is not seen universally
but in a certain patient populations. Therefore, identifying the specific patient population that would
respond to PD-L1 blockade or show resistance is key to developing treatment strategies. In a large
cohort (observational) study of patients with metastatic urothelial carcinoma (mUC- a form of bladder
cancer), tumor response was examined while the patients were treated with a anti PD-L1 drug called
atezolizumab. The results fell into two categories; response or lack of response, each with individual
criteria. Responsive cells would show high Tumor mutational burden (TMB), which is a biological
marker that measures the number of mutations in a tumor genome. A tumor with high TMB has a
greater chance of responding to drugs that use the host's own immune system to kill cancer cells
(immunotherapies). A lack of response would be characterized by signaling in fibroblast cells by a
protein called TGF-Beta. The signaling leads to a common physical appearance (phenotype) of
collagen rich cells in the tumor. We found that administering a TGF-Beta blocking antibody together
with a anti PD-L1 allowed for easier penetration of T cells, reduced signaling by TGF Beta in stromal
cells, and regression of the tumor.