HLA genotype affects response: Immunotherapy works by activating the patient's own immune system to fight cancer. For effective tumor killing, CD8 ⁺ T cells recognize tumor peptides presented by human leukocyte antigen class I (HLA-I) molecules. In humans, there are three major HLA-I genes ( HLA-A, HLA-B , and HLA-C ). Chowell et al. asked whether germline HLA-I genotype influences how T cells recognize tumor peptides and respond to checkpoint inhibitor immunotherapies (see the Perspective by Kvistborg and Yewdell). They examined more than 1500 patients and found that heterozygosity at HLA-I loci was associated with better survival than homozygosity for one or more HLA-I genes. Thus, specific HLA-I mutations could have implications for immune recognition and for the design of epitopes for cancer vaccines and immunotherapies. Science , this issue p. 582 ; see also p. 516

Recent clinical trials have demonstrated a clear survival advantage in advanced head and neck squamous cell carcinoma (HNSCC) patients treated with immune checkpoint blockade. These emerging results reveal that HNSCC is one of the most promising frontiers for immunotherapy research. However, further progress in head and neck immuno-oncology will require a detailed understanding of the immune infiltrative landscape found in these tumors. We leveraged transcriptome data from 280 tumors profiled by The Cancer Genome Atlas (TCGA) to comprehensively characterize the immune landscape of HNSCC in order to develop a rationale for immunotherapeutic strategies in HNSCC and guide clinical investigation. We find that both HPV ⁺ and HPV ^– HNSCC tumors are among the most highly immune-infiltrated cancer types. Strikingly, HNSCC had the highest median Treg/CD8 ⁺ T cell ratio and the highest levels of CD56 ^dim NK cell infiltration, in our pan-cancer analysis of the most immune-infiltrated tumors. CD8 ⁺ T cell infiltration and CD56 ^dim NK cell infiltration each correlated with superior survival in HNSCC. Tumors harboring genetic smoking signatures had lower immune infiltration and were associated with poorer survival, suggesting these patients may benefit from immune agonist therapy. These findings illuminate the immune landscape of HPV ⁺ and HPV ^– HNSCC. Additionally, this landscape provides a potentially novel rationale for investigation of agents targeting modulators of Tregs (e.g., CTLA-4, GITR, ICOS, IDO, and VEGFA) and NK cells (e.g., KIR, TIGIT, and 4-1BB) as adjuncts to anti–PD-1 in the treatment of advanced HNSCC.

High mutational load gets a response: Cancers harbor many genetic mutations. Defects in DNA mismatch repair prevent tumors from repairing certain types of DNA damage and lead to a hypermutable genomic state known as microsatellite instability (MSI). Some tumors with a high degree of MSI may be treatable with PD-1 (programmed cell death–1) immunotherapy, but patient response is highly variable. Mandal et al. studied drivers of differential response to immunotherapy in these patients and found that MSI intensity and insertion-deletion mutations strongly affected therapeutic outcome. Science , this issue p. 485

Treatment with immune checkpoint inhibitors (ICI) has demonstrated clinical benefit for a wide range of cancer types. Because only a subset of patients experience clinical benefit, there is a strong need for biomarkers that are easily accessible across diverse practice settings. Here, in a retrospective cohort study of 1714 patients with 16 different cancer types treated with ICI, we show that higher neutrophil-to-lymphocyte ratio (NLR) is significantly associated with poorer overall and progression-free survival, and lower rates of response and clinical benefit, after ICI therapy across multiple cancer types. Combining NLR with tumor mutational burden (TMB), the probability of benefit from ICI is significantly higher (OR = 3.22; 95% CI, 2.26-4.58; P < 0.001) in the NLR low/TMB high group compared to the NLR high/TMB low group. NLR is a suitable candidate for a cost-effective and widely accessible biomarker, and can be combined with TMB for additional predictive capacity.

Background: The rapidly rising incidence of papillary thyroid cancer may be due to overdiagnosis of a reservoir of subclinical disease. To conclude that overdiagnosis is occurring, evidence for an association between access to health care and the incidence of cancer is necessary. Methods: We used Surveillance, Epidemiology, and End Results (SEER) data to examine U.S. papillary thyroid cancer incidence trends in Medicare-age and non–Medicare-age cohorts over three decades. We performed an ecologic analysis across 497 U.S. counties, examining the association of nine county-level socioeconomic markers of health care access and the incidence of papillary thyroid cancer. Results: Papillary thyroid cancer incidence is rising most rapidly in Americans over age 65 years (annual percentage change, 8.8%), who have broad health insurance coverage through Medicare. Among those under 65, in whom health insurance coverage is not universal, the rate of increase has been slower (annual percentage change, 6.4%). Over three decades, the mortality rate from thyroid cancer has not changed. Across U.S. counties, incidence ranged widely, from 0 to 29.7 per 100,000. County papillary thyroid cancer incidence was significantly correlated with all nine sociodemographic markers of health care access: it was positively correlated with rates of college education, white-collar employment, and family income; and negatively correlated with the percentage of residents who were uninsured, in poverty, unemployed, of nonwhite ethnicity, non-English speaking, and lacking high school education. Conclusion: Markers for higher levels of health care access, both sociodemographic and age-based, are associated with higher papillary thyroid cancer incidence rates. More papillary thyroid cancers are diagnosed among populations with wider access to healthcare. Despite the threefold increase in incidence over three decades, the mortality rate remains unchanged. Together with the large subclinical reservoir of occult papillary thyroid cancers, these data provide supportive evidence for the widespread overdiagnosis of this entity.