CD106 in tumor-specific exhausted CD8+ T cells mediates immunosuppression by inhibiting TCR signaling.

T cell exhaustion is a major contributor to immunosuppression in the tumor microenvironment (TME). Blockade of key regulators of T cell exhaustion, such as PD-1, can reinvigorate tumor-specific T cells and activate anti-tumor immunity in various types of cancer. Here, we identified that CD106 was specifically expressed in exhausted CD8+ T cells in the TME using single-cell RNA-sequencing. High CD106 expression in the TME in clinical samples corresponded to improved response to cancer immunotherapy. CD106 in tumor-specific T cells suppressed anti-tumor immunity both in vitro and in vivo, and loss of CD106 in CD8+ T cells suppressed tumor growth and improved response to PD-1 blockade. Mechanistically, CD106 inhibited T-cell receptor (TCR) signaling by interacting with the TCR/CD3 complex and reducing its surface expression. Together, these findings provide insights into the immunosuppressive role of CD106 expressed in tumor-specific exhausted CD8+ T cells, identifying it as a potential biomarker and therapeutic target for cancer immunotherapy.

Long-term follow-up results from KEYNOTE-041: Phase 1b study of pembrolizumab in Japanese patients with advanced melanoma.

Pembrolizumab demonstrated an acceptable safety profile and promising antitumor activity in Japanese patients with advanced melanoma in the phase 1b KEYNOTE-041 (Study of Pembrolizumab [MK-3475] in Participants With Advanced Melanoma) trial. To evaluate the long-term efficacy and safety of pembrolizumab in Japanese patients with advanced melanoma in KEYNOTE-041. The current analysis reports results of additional follow-up of approximately 12 months since the initial analysis. Eligible patients had locally advanced (unresectable stage III) or metastatic (stage IV) melanoma not amenable to local therapy and had received two or fewer prior systemic therapies. Pembrolizumab 2 mg/kg was given every 3 weeks for up to 2 years or until confirmed progression or unacceptable toxicity. Primary end points included safety, tolerability, and overall response rate (ORR) per Response Evaluation Criteria in Solid Tumors version 1.1 by independent central review. The data cutoff for this analysis was August 30, 2017. Forty-two patients were followed up for a median of 22.3 months (range, 2.63-30.82 months). The ORR was 24.3% (nine of 37 evaluable patients [95% confidence interval (CI), 11.8%-41.2%]). Two patients with partial response at the time of the initial analysis achieved complete response. The median overall survival (OS) was 25.1 months (95% CI, 13.1-not reached] and the 30-month OS rate was 46.3% (95% CI, 29.8%-61.3%). The median duration of response was not reached. Treatment-related adverse events (TRAEs) were reported in 78.6% of patients; the incidence of grade 3 to 5 TRAEs was 23.8%. No additional treatment-related deaths occurred since the initial analysis. Pembrolizumab provided durable antitumor activity and an acceptable safety profile in Japanese patients with advanced melanoma.

Stem-like progenitor and terminally differentiated TFH-like CD4+ T cell exhaustion in the tumor microenvironment.

Immune checkpoint inhibitors exert clinical efficacy against various types of cancer through reinvigoration of exhausted CD8+ T cells that attack cancer cells directly in the tumor microenvironment (TME). Using single-cell sequencing and mouse models, we show that CXCL13, highly expressed in tumor-infiltrating exhausted CD8+ T cells, induces CD4+ follicular helper T (TFH) cell infiltration, contributing to anti-tumor immunity. Furthermore, a part of the TFH cells in the TME exhibits cytotoxicity and directly attacks major histocompatibility complex-II-expressing tumors. TFH-like cytotoxic CD4+ T cells have high LAG-3/BLIMP1 and low TCF1 expression without self-renewal ability, whereas non-cytotoxic TFH cells express low LAG-3/BLIMP1 and high TCF1 with self-renewal ability, closely resembling the relationship between terminally differentiated and stem-like progenitor exhaustion in CD8+ T cells, respectively. Our findings provide deep insights into TFH-like CD4+ T cell exhaustion with helper progenitor and cytotoxic differentiated functions, mediating anti-tumor immunity orchestrally with CD8+ T cells.

Current surgical management for melanoma.

Melanoma is a major malignant cutaneous neoplasm with a high mortality rate. In recent years, the treatment of melanoma has developed dramatically with the invention of new therapeutic agents, including immune checkpoint inhibitors and molecular-targeted agents. These agents are available as adjuvant therapies for postoperative patients with stage IIB, IIC, and III melanomas. Furthermore, neoadjuvant therapy has been studied in several global clinical trials and has demonstrated promising and favorable clinical efficacy, mainly in patients with palpable regional lymph nodes. A recent large phase III clinical trial investigating early lymph node dissection for sentinel lymph node metastases demonstrated no survival benefits. Based on these data, surgery should be reconsidered as an appropriate treatment modality for melanoma. The need for invasive surgical procedures will be reduced with the invention of effective adjuvant and neoadjuvant therapies and novel clinical trial data on regional lymph node dissection. However, surgery still plays an important role in treating early-stage melanoma, accurately determining the disease stage, and effective palliative treatment for advanced melanoma. In this article, we focus on surgery for primary tumors, regional lymph nodes, and metastatic sites in an era of remarkably revolutionary drug treatments for melanoma.

Efficacy of salvage therapies for advanced acral melanoma after anti-PD-1 monotherapy failure: a multicenter retrospective study of 108 Japanese patients.

Background: Anti-programmed cell death protein 1 (PD-1) monotherapy is one of the standard systemic therapies for advanced melanoma; however, the efficacy of salvage systemic therapies after PD-1 monotherapy failure (PD-1 MF), particularly in acral melanoma (AM), the main clinical melanoma type in Japanese patients, is unclear. This study aimed to investigate the efficacy of salvage systemic therapies in Japanese patients with AM after PD-1 MF. Patients and methods: The study included 108 patients with advanced AM (palm and sole, 72; nail apparatus, 36) who underwent salvage systemic therapy at 24 Japanese institutions. We mainly assessed the objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). Results: Thirty-six (33%) patients received ipilimumab, 23 (21%) received nivolumab and ipilimumab (nivo/ipi), 10 (9%) received cytotoxic chemotherapy, 4 (4%) received BRAF and MEK inhibitors (BRAFi/MEKi), and the remaining 35 (32%) continued with PD-1 monotherapy after disease progression. The ORRs in the ipilimumab, nivo/ipi, cytotoxic chemotherapy, and BRAFi/MEKi groups were 8, 17, 0, and 100%, respectively. The nivo/ipi group showed the longest OS (median, 18.9 months); however, differences in ORR, PFS, and OS between the groups were insignificant. The OS in the nivo/ipi group was higher in the palm and sole groups than in the nail apparatus group (median: not reached vs. 8.7 months, p < 0.001). Cox multivariate analysis demonstrated that nail apparatus melanoma independently predicted unfavorable PFS and OS (p = 0.006 and 0.001). The total OS (from PD-1 monotherapy initiation to death/last follow-up) was insignificant between the groups. Conclusion: Nivo/ipi was not more effective than cytotoxic chemotherapy and ipilimumab after PD-1 MF in patients with advanced AM. The prognosis after PD-1 MF would be poorer for nail apparatus melanoma than for palm and sole melanoma.

Systemic therapy for Asian patients with advanced BRAF V600-mutant melanoma in a real-world setting: A multi-center retrospective study in Japan (B-CHECK-RWD study).

BACKGROUND: Anti-PD-1-based immunotherapy is considered a preferred first-line treatment for advanced BRAF V600-mutant melanoma. However, a recent international multi-center study suggested that the efficacy of immunotherapy is poorer in Asian patients in the non-acral cutaneous subtype. We hypothesized that the optimal first-line treatment for Asian patients may be different. METHODS: We retrospectively collected data of Asian patients with advanced BRAF V600-mutant melanoma treated with first-line BRAF/MEK inhibitors (BRAF/MEKi), anti-PD-1 monotherapy (Anti-PD-1), and nivolumab plus ipilimumab (PD-1/CTLA-4) between 2016 and 2021 from 28 institutions in Japan. RESULTS: We identified 336 patients treated with BRAF/MEKi (n = 236), Anti-PD-1 (n = 64) and PD-1/CTLA-4 (n = 36). The median follow-up duration was 19.9 months for all patients and 28.6 months for the 184 pa tients who were alive at their last follow-up. For patients treated with BRAF/MEKi, anti-PD-1, PD-1/CTLA-4, the median ages at baseline were 62, 62, and 53 years (p = 0.03); objective response rates were 69%, 27%, and 28% (p < 0.001); median progression-free survival (PFS) was 14.7, 5.4, and 5.8 months (p = 0.003), and median overall survival (OS) was 34.6, 37.0 months, and not reached, respectively (p = 0.535). In multivariable analysis, hazard ratios (HRs) for PFS of Anti-PD-1 and PD-1/CTLA-4 compared with BRAF/MEKi were 2.30 (p < 0.001) and 1.38 (p = 0.147), and for OS, HRs were 1.37 (p = 0.111) and 0.56 (p = 0.075), respectively. In propensity-score matching, BRAF/MEKi showed a tendency for longer PFS and equivalent OS with PD-1/CTLA-4 (HRs for PD-1/CTLA-4 were 1.78 [p = 0.149]) and 1.03 [p = 0.953], respectively). For patients who received second-line treatment, BRAF/MEKi followed by PD-1/CTLA-4 showed poor survival outcomes. CONCLUSIONS: The superiority of PD-1/CTLA-4 over BRAF/MEKi appears modest in Asian patients. First-line BRAF/MEKi remains feasible, but it is difficult to salvage at progression. Ethnicity should be considered when selecting systemic therapies until personalized biomarkers are available in daily practice. Further studies are needed to establish the optimal treatment sequence for Asian patients.

Simultaneous development of generalized pustular psoriasis and pemphigoid with multiple autoantibodies in a complete responder of pembrolizumab for lung cancer.

Patients with psoriasis vulgaris have a higher incidence of pemphigoid than the general population. However, there are only a few concise reports on the coexistence of generalized pustular psoriasis (GPP) and pemphigoid. The authors describe a rare case of the simultaneous development of GPP and pemphigoid with multiple autoantibodies (i.e., BP180-C-terminal, 200-kDa protein, and laminin 332 proteins) in a complete responder of immune checkpoint inhibitor (ICI) treatment for lung cancer. Anti-interleukin 17 inhibitors for the GPP and oral corticosteroids at 10 mg/day for the pemphigoid effectively achieved remission in both diseases. It may not be uncommon to detect multiple autoantibodies in patients with pemphigoid; however, the detection of autoantibodies to more than three antigens in a single patient is relatively rare. In the current patient, the severe inflammation of GPP might have generated multiple autoantibodies. In addition, although pembrolizumab achieved a complete response and was discontinued 9 months before the onset of GPP and pemphigoid, the ICI might have affected the development of the two diseases. This case report adds useful information to the limited knowledge regarding the coexistence of GPP and pemphigoid, and aids in a better understanding of the pathological mechanisms and treatment options for such patients. Furthermore, the possibility that more patients may develop multiple autoimmune and autoinflammatory diseases in the era of ICIs should be recognized.

Analyzing the relationship between the efficacy of first-line immune checkpoint inhibitors and cumulative sun damage in Japanese patients with advanced BRAF wild-type nonacral cutaneous melanoma: A retrospective real-world, multicenter study.

BACKGROUND: Efficacy of anti-PD-1 antibody monotherapy (PD1) or anti-PD-1 plus anti-CTLA-4 combination therapy (PD1 +CTLA4) for melanoma is affected by its clinical subtype. The amount of tumor mutation burden (TMB) caused by cumulative sun damage (CSD) is occasionally used to explain this; however, their relationship in Japanese nonacral cutaneous melanoma (NACM) is still unclear. OBJECTIVE: To analyze the ICI efficacy and its relationship with CSD of the primary lesion in Japanese patients with NACM. METHODS: Japanese patients with advanced BRAF wild-type NACM who received first-line ICIs were recruited. Objective response rate (ORR), progression-free survival (PFS), and overall survival (OS), and the degree of solar elastosis (SE) were evaluated. RESULTS: A total of 146 patients (PD1 group 113 and PD1 +CTLA4 group 33) were included. No significant differences in ORR were observed between the PD1 and PD1 +CTLA4 groups (35 % vs. 36 %; P = 0.67) or PFS and OS (median PFS 6.1 months vs. 8.5 months; P = 0.46, median OS 28.1 months vs. not reached; P = 0.59). Multivariate survival analysis revealed that PD1 +CTLA4 did not prolong the PFS and OS. The SE score had no effect on either PFS or OS. CONCLUSIONS: ICI efficacy was not as high as those reported in Western countries, and PD1 +CTLA4 did not present better clinical efficacy compared to PD1. Indicators of CSD did not serve as a predictor for clinical advantage. These findings may partially support the theory that ICI efficacy is affected by CSD; however, other unrecognized factors may also exist.

High Expression of MHC Class I Overcomes Cancer Immunotherapy Resistance Due to IFNγ Signaling Pathway Defects.

IFNγ signaling pathway defects are well-known mechanisms of resistance to immune checkpoint inhibitors. However, conflicting data have been reported, and the detailed mechanisms remain unclear. In this study, we have demonstrated that resistance to immune checkpoint inhibitors owing to IFNγ signaling pathway defects may be primarily caused by reduced MHC-I expression rather than by the loss of inhibitory effects on cellular proliferation or decreased chemokine production. In particular, we found that chemokines that recruit effector T cells were mainly produced by immune cells rather than cancer cells in the tumor microenvironment of a mouse model, with defects in IFNγ signaling pathways. Furthermore, we found a response to immune checkpoint inhibitors in a patient with JAK-negative head and neck squamous cell carcinoma whose HLA-I expression level was maintained. In addition, CRISPR screening to identify molecules associated with elevated MHC-I expression independent of IFNγ signaling pathways demonstrated that guanine nucleotide-binding protein subunit gamma 4 (GNG4) maintained MHC-I expression via the NF-κB signaling pathway. Our results indicate that patients with IFNγ signaling pathway defects are not always resistant to immune checkpoint inhibitors and highlight the importance of MHC-I expression among the pathways and the possibility of NF-κB-targeted therapies to overcome such resistance. See related Spotlight by Haugh and Daud, p. 864.

Trends in mortality and morbidity in patients with bullous pemphigoid before and after approval of intravenous immunoglobulin in Japan: an interrupted time-series analysis.

BACKGROUND: Intravenous immunoglobulin (IVIg) has been reported to be an effective treatment for bullous pemphigoid. However, the impact of IVIg approval on real-world outcomes remains unclear. OBJECTIVES: To investigate the effect of IVIg approval on patients with bullous pemphigoid using a national inpatient database. METHODS: Using the Japanese Diagnosis Procedure Combination database, we identified 14 229 patients admitted to hospital for bullous pemphigoid and treated with systemic corticosteroids between July 2010 and March 2020. We conducted an interrupted time-series analysis to compare in-hospital mortality and morbidity between the patients admitted before and after the approval of reimbursement of IVIg for bullous pemphigoid in the Japanese universal health insurance system in November 2015. RESULTS: In-hospital mortality was 5.5% before and 4.5% after the approval of IVIg reimbursement. After the IVIg approval, 18% of the patients were treated with IVIg. Based on the interrupted time-series analysis, in-hospital mortality significantly decreased at the time of approval [-1.2%, 95% confidence interval (CI) -2.0 to -0.3, P = 0.009] and a downward trend was observed after the approval (-0.4% annual rate, 95% CI -0.7 to -0.1, P = 0.005). In-hospital morbidity also demonstrated a downward trend after the approval. CONCLUSIONS: IVIg approval is associated with lower in-hospital mortality and morbidity in inpatients with bullous pemphigoid.

Adoptive cell transfer therapy for melanoma.

Adoptive cell transfer (ACT) of tumor-infiltrating lymphocytes (TILs) for melanoma is an example of the most successful cancer immune therapy. It achieves a durable complete response about ~20% of patients, and they might be cured. However, the ratio of patients with durable benefits is not high, and its complicated procedure prevents its diffusion. Therefore, many efforts to enhance the effect and simplify the protocol of TIL therapy have been made so far, resulting in the establishment of a simple and effective current TIL therapy that has been propagated to other institutes and countries. Moreover, TIL therapy and translational research using clinical samples derived from durable responders elucidate the important element for developing more effective cancer immune therapies in the future. This review introduced the brief history, attempts for the improvement and important findings elucidated by translational research of ACT for melanoma.

Clinical course and outcomes of pemphigus vulgaris and foliaceus: A retrospective study using a nationwide database in Japan.

Pemphigus is a life-threatening autoimmune blistering disease. Patient characteristics, treatment courses, and outcomes remain unclear owing to its rarity. To describe the background, treatment, and outcomes of pemphigus, we identified 2598 patients with pemphigus vulgaris and 1186 patients with pemphigus foliaceus from a nationwide inpatient database in Japan. Patients with pemphigus vulgaris were younger (62 vs 72 years, P < 0.001), had fewer comorbidities, and were more likely to be admitted to high-volume hospitals (38% vs 30%, P < 0.001) than those with pemphigus foliaceus. Patients with pemphigus vulgaris had undergone more aggressive treatment, including steroid pulse therapy, intravenous immunoglobulin, or plasmapheresis, compared with those with pemphigus foliaceus (48% vs 42%, P = 0.001); specifically, in patients aged <70 years, the pemphigus vulgaris group was more likely to undergo aggressive treatment than the pemphigus foliaceus group (52% vs 45%), whereas there was no significant difference in patients aged ≥70 years (40% vs 40%). Immunosuppressive agents (30% vs 26%, P = 0.015) and analgesics, including opioids (45% vs 36%, P < 0.001), were used more frequently, whereas topical corticosteroids were used less frequently (32% vs 48%, P < 0.001) in patients with pemphigus vulgaris compared with those with pemphigus foliaceus. In-hospital mortality was lower in patients with pemphigus vulgaris than in those with pemphigus foliaceus (2.2% vs 4.0%, P = 0.002); in the comparison stratified by age, the mortality was equivalent among the two groups (0.6% in patients aged <70 years and 6.1% in those aged ≥70 years). Overall, patients with pemphigus vulgaris had a 10-day longer hospitalization period and higher hospitalization costs than those with pemphigus foliaceus. Our findings provide useful information for understanding the current trends in the management of pemphigus in Japan.

Efficacy comparison between anti-PD-1 antibody monotherapy and anti-PD-1 plus anti-CTLA-4 combination therapy as first-line immunotherapy for advanced acral melanoma: A retrospective, multicenter study of 254 Japanese patients.

BACKGROUND: Although anti-PD-1 antibody monotherapy (PD-1) is commonly used to treat advanced acral melanoma (AM), its efficacy is limited. Further, data on the efficacy of PD-1 plus anti-CTLA-4 antibody (PD-1+CTLA-4) for the treatment of AM are limited. Therefore, we compared the efficacy of PD-1+CTLA-4 and PD-1 in the treatment of Japanese patients with advanced AM. METHODS: This retrospective study evaluated patients with advanced AM who were treated with PD-1 or PD-1+CTLA-4 as first-line immunotherapy in 24 Japanese institutions between 2014 and 2020. Treatment efficacy focussing on the objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) was compared between the two groups. RESULTS: In total, 254 patients (palm and sole melanoma [PSM], n = 180; nail apparatus melanoma [NAM], n = 74) were included. Among the patients with PSM, the ORR (19% vs. 31%; P = 0.44), PFS (5.9 vs. 3.2 months; P = 0.74), and OS (23.1 vs. not reached; P = 0.55) did not differ significantly between the PD-1 and PD-1+CTLA-4 groups. Among the patients with NAM, the ORR (61% vs. 10%; P < 0.001) was significantly higher and PFS was longer (6.4 vs. 3.8 months; P = 0.10) in the PD-1+CTLA-4 group than in the PD-1 group. Cox multivariate analysis demonstrated that PD-1+CTLA-4 is an independent predictor of a favourable PFS in patients with NAM (P = 0.002). CONCLUSIONS: The efficacy of PD-1+CTLA-4 is not superior to that of PD-1 for the treatment of advanced PSM. However, PD-1+CTLA-4 may be more efficacious than PD-1 for the treatment of advanced NAM.

PD-1 blockade therapy promotes infiltration of tumor-attacking exhausted T cell clonotypes.

PD-1 blockade exerts clinical efficacy against various types of cancer by reinvigorating T cells that directly attack tumor cells (tumor-specific T cells) in the tumor microenvironment (TME), and tumor-infiltrating lymphocytes (TILs) also comprise nonspecific bystander T cells. Here, using single-cell sequencing, we show that TILs include skewed T cell clonotypes, which are characterized by exhaustion (Tex) or nonexhaustion signatures (Tnon-ex). Among skewed clonotypes, those in the Tex, but not those in the Tnon-ex, cluster respond to autologous tumor cell lines. After PD-1 blockade, non-preexisting tumor-specific clonotypes in the Tex cluster appear in the TME. Tumor-draining lymph nodes (TDLNs) without metastasis harbor a considerable number of such clonotypes, whereas these clonotypes are rarely detected in peripheral blood. We propose that tumor-infiltrating skewed T cell clonotypes with an exhausted phenotype directly attack tumor cells and that PD-1 blockade can promote infiltration of such Tex clonotypes, mainly from TDLNs.

Mixed Response to Cancer Immunotherapy is Driven by Intratumor Heterogeneity and Differential Interlesion Immune Infiltration.

Some patients experience mixed response to immunotherapy, whose biological mechanisms and clinical impact have been obscure. We obtained two tumor samples from lymph node (LN) metastatic lesions in a same patient. Whole exome sequencing for the both tumors and single-cell sequencing for the both tumor-infiltrating lymphocytes (TIL) demonstrated a significant difference in tumor clonality and TILs' characteristics, especially exhausted T-cell clonotypes, although a close relationship between the tumor cell and T-cell clones were observed as a response of an overlapped exhausted T-cell clone to an overlapped neoantigen. To mimic the clinical setting, we generated a mouse model of several clones from a same tumor cell line. Similarly, differential tumor clones harbored distinct TILs, and one responded to programmed cell death protein 1 (PD-1) blockade but the other did not in this model. We further conducted cohort study (n = 503) treated with PD-1 blockade monotherapies to investigate the outcome of mixed response. Patients with mixed responses to PD-1 blockade had a poor prognosis in our cohort. Particularly, there were significant differences in both tumor and T-cell clones between the primary and LN lesions in a patient who experienced tumor response to anti-PD-1 mAb followed by disease progression in only LN metastasis. Our results underscore that intertumoral heterogeneity alters characteristics of TILs even in the same patient, leading to mixed response to immunotherapy and significant difference in the outcome. Significance: Several patients experience mixed responses to immunotherapies, but the biological mechanisms and clinical significance remain unclear. Our results from clinical and mouse studies underscore that intertumoral heterogeneity alters characteristics of TILs even in the same patient, leading to mixed response to immunotherapy and significant difference in the outcome.