Genentech challenges to the classical hypothesis on immune evasion

Cancer immunotherapy has been the topic of much debate in recent years. Five papers on PD-1 blockades have been published in the latest issue of Nature[1]. Scientists from Genentech reported their unexpected findings on the anti-PDL1 antibody MPDL3280A[2].

Researchers have made massive efforts to look for biomarkers which could predict the clinical response to PD-1 blockades. The expression of PDL1 in tumor cells attracts the most attention, although it is not a binary, static predictive marker.

Unexpectedly, Genentech reported that the association of tumor-infiltrating immune cell PDL1 expression with treatment response appeared stronger than that with tumor cell PDL1 expression.

Take NSCLC for example: 83% of patients with PDL1 positive (immunohistochemistry score 3) tumor-infiltrating immune cells responded to MPDL3280A; only 38% of patients with PDL1 positive tumor cells responded.

According to the classical hypothesis on immune evasion[3], interferon-γ induces protective expression of PDL1 on the surface of tumor cells which in turn suppresses the T cell responses.

Genentech’s findings suggest that the pre-existing T-cell responses before treatment may be mainly suppressed by PDL1 positive tumour-infiltrating immune cells (macrophages, dendritic cells, T cells), but not tumor cells. Immune cells in the tumor microenvironment self-limit the anti-tumor response.

[1] Nature. 2014, 515(7528), 496-498.

[2] Nature. 2014, 515(7528), 563-567.

[3] Nat Med. 2002, 8(8), 793-800.

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