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How T cells decide to attack. A T cell needs to see the target (TCR-MHC) and get a 'go' signal (CD28). PD-1 and CTLA-4 are 'stop' signals; tumours exploit them. Checkpoint inhibitors remove the stop.
Dendritic cells prime T cells in lymph nodes via peptide-MHC to TCR (signal 1) plus B7 to CD28 (signal 2); CTLA-4 competes for B7 and terminates priming. In the tumour, interferon-gamma from activated T cells induces PD-L1 on tumour and myeloid cells, which engages PD-1 on T cells and inhibits their effector function (adaptive resistance). LAG-3, TIM-3, TIGIT are further exhaustion checkpoints. Anti-CTLA-4 acts at priming; anti-PD-1/PD-L1 in the tumour. Predictors: PD-L1, TMB, MSI, TILs, interferon signatures. Resistance: loss of MHC-I/B2M, JAK1/2, antigen loss, immunosuppressive myeloid cells, TGF-β exclusion.
A soldier needs a target in the sights (TCR) and an order to fire (CD28). CTLA-4 is a commander revoking orders during training; PD-1 is a white flag the enemy waves on the battlefield that makes the soldier lower their weapon. Checkpoint inhibitors tear up the white flag.
The first credible response signal in microsatellite stable colorectal cancer, and the reason the field's attention has moved to Fc engineering and to excluding patients with active liver metastases, in whom responses are rare.
For colon cancer that is mismatch-repair deficient (about 10-15% of colon cancers, more in older patients), a single short course of immunotherapy before surgery is now a reasonable standard and is far more effective than chemotherapy, which has little effect in this subtype. It requires testing every colon cancer for mismatch repair at diagnosis, before surgery. Whether some patients can safely skip surgery, as in dMMR rectal cancer, is the next question.
It is the positive half of the tumour mutational burden story and it applies only to single-agent immunotherapy, which is the setting fewest patients are treated in.
This is the result that ended tumour mutational burden as a practical selector in lung cancer: in the regimen most patients receive, it selects nobody, and neither do the co-mutations most often quoted as reasons to withhold immunotherapy.
It is the strongest case that mutation burden is real biology in lung cancer and, at the same time, the clearest demonstration that its threshold is not fixed, which is why it never became a reliable selector.
Cercek's dostarlimab study is the clearest demonstration that immunotherapy can replace surgery in a solid tumour: patients with dMMR rectal cancer can keep their rectum and avoid the permanent effects of pelvic radiotherapy and surgery. Non-operative management after PD-1 blockade is now in guidelines for this group, and MMR testing before treatment of rectal cancer is essential. The approach applies only to the 5-10% of rectal cancers that are dMMR.
It corrected a widely repeated simplification. An STK11 or KEAP1 mutation is not by itself a reason to expect immunotherapy to fail; it is a reason to expect it in a KRAS-mutant tumour, which is how the result should be read on a report.
It offers the first credible explanation for why only a minority of small-cell patients get a durable benefit from checkpoint blockade, and it introduces subtype switching, which would mean retesting at relapse rather than typing once.
Shares Safety and activity of anti-PD-L1 antibody in patients with advanced cancer, Autophagy promotes immune evasion of pancreatic cancer by degrading MHC-I, Phase 2 trial of single agent ipilimumab (anti-CTLA-4) for locally advanced or metastatic pancreatic adenocarcinoma, Challenges and opportunities for pancreatic cancer immunotherapy.
Shares Challenges and opportunities for pancreatic cancer immunotherapy, Atezolizumab with or without cobimetinib versus regorafenib in previously treated metastatic colorectal cancer (IMblaze370), B7-H4 (VTCN1), Targeting CXCL12 from FAP-expressing carcinoma-associated fibroblasts synergizes with anti-PD-L1 immunotherapy in pancreatic cancer.
Shares Blood-based tumor mutational burden as a predictor of clinical benefit in non-small-cell lung cancer patients treated with atezolizumab, CheckMate 026: first-line nivolumab in stage IV or recurrent non-small-cell lung cancer, Nivolumab plus Ipilimumab in Lung Cancer with a High Tumor Mutational Burden, Associations of tissue tumour mutational burden and mutational status with clinical outcomes with pembrolizumab plus chemotherapy versus chemotherapy for metastatic non-small-cell lung cancer.
Shares Blood-based tumor mutational burden as a predictor of clinical benefit in non-small-cell lung cancer patients treated with atezolizumab, CheckMate 026: first-line nivolumab in stage IV or recurrent non-small-cell lung cancer, Nivolumab plus Ipilimumab in Lung Cancer with a High Tumor Mutational Burden, Associations of tissue tumour mutational burden and mutational status with clinical outcomes with pembrolizumab plus chemotherapy versus chemotherapy for metastatic non-small-cell lung cancer.
Shares Circadian control, Basal cell carcinoma (KEGG map), Endometrial cancer (KEGG map), Melanoma (KEGG map).
Shares A prospective, multi-institutional, pathologist-based assessment of 4 immunohistochemistry assays for PD-L1 expression in non-small cell lung cancer, PD-L1 Immunohistochemistry Assays for Lung Cancer: Results from Phase 1 of the Blueprint PD-L1 IHC Assay Comparison Project, PD-L1 immunohistochemistry comparability study in real-life clinical samples: results of Blueprint phase 2 project, Association of high tumor mutation burden in non-small cell lung cancers with increased immune infiltration and improved clinical outcomes of PD-L1 blockade across PD-L1 expression levels.
Shares PD-1 blockade + VEGF inhibition, Bladder cancer (KEGG map), Renal cell carcinoma (KEGG map), Hepatocellular carcinoma (KEGG map).
Shares Time immunotherapy to the moment targeted drugs make tumours visible, PD-L1 Immunohistochemistry Assays for Lung Cancer: Results from Phase 1 of the Blueprint PD-L1 IHC Assay Comparison Project, Leach, Krummel and Allison: releasing the CTLA-4 brake makes mice reject tumours, Iwai and Honjo: tumours use PD-L1 to escape T cells, and blocking it restores attack.