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Why aren't immune checkpoint inhibitors working for every patient?

Immune checkpoint system stands for the inhibitory receptors that appear on our immune cells (and their ligands on normal tissue cells) that work as "immunological brakes". In physiological condition, such mechanism ensures that the functions of immune cells will get buffered and thus will not impair normal cells surrounding them. The best-known inhibitory receptors are Program Death-1 (PD-1) and Cytotoxic-T lymphocyte-associated protein 4 (CTLA-4) that are expressed on most immune cell types.

However, when it comes to cancer condition, immune checkpoints can also be hijacked by cancer cells to protect themselves from immune surveillance. Notably, some cancer cells highly express the ligands of these inhibitory receptors. So imagine in optimal condition, a immune cell can recognize a tumor cell, get activated and can eventually kill it. But when cancer cells trigger the inhibitory pathways of immune cells by directly binding to the PD-1 and CTLA-4 receptors on them, cancer cells can escape immune surveillance.

One of the hottest anti-cancer treatments that both pharmaceutical companies and research institutes are rigorously studying is immune checkpoint blockage. Pembrolizumab is developed by Roche to block the PD-1 pathways while Bristol-Myers Squibb also has its commercialized PD-1 inhibitor Nivolumab. These drugs have shown encouraging results treating melanoma and non-small cell lung cancer (NSCLC) and they are being clinically studied in treating other types of cancers. 

Though these immune checkpoint inhibitors are truly blowing our mind in evolutionizing cancer treatment, they only work for a set of patients while the others don't really respond.. Why is it so?

Several most recent studies have provided some hints of the myth. A study from MSKCC compared a cohort of NSCLC patients that either gained benefit from PD-1 inhibitor treatment or not. It found that when a patient carries more mutations that render more neo-antigens, he/she tends to have a better result from the immunotherapy(1Snyder, Makarov et al. 2014). Another studied on melanoma patients suggested that the pre-existing immune cells in tumor can serve as a good indicate that PD-1 inhibitor would work for the patient(Tumeh, Harview et al. 2014). So it appears that immune checkpoint can only work to potentiate the pre-existed immune cells that are functionally inhibited. 

One latest study by a group from University of Chicago published their result in Nature that suggested that activation of a specific pathway (here as WNT/beta-catenin pathway) in melanoma tumor cells can inhibit the immune cell infiltration to tumor sites. (Spranger, Bao et al. 2015) In such case, melanoma patients with high beta-catenin wouldn’t respond to PD-1 inhibiting treatment. The study provides a very intriguing mechanism that tumor cells can inhibit the trafficking and infiltration of immune cells. So if we can use combo therapy by targeting both PD-1 and beta-catenin pathways, maybe we can treat the originally non-responsive patients?!



Snyder, A., et al. (2014). "Genetic basis for clinical response to CTLA-4 blockade in melanoma." N Engl J Med 371(23): 2189-2199.
           
Spranger, S., et al. (2015). "Melanoma-intrinsic [bgr]-catenin signalling prevents anti-tumour immunity." Nature advance online publication.
           
Tumeh, P. C., et al. (2014). "PD-1 blockade induces responses by inhibiting adaptive immune resistance." Nature 515(7528): 568-571.
           






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