RESUMO
BACKGROUND/AIM: Development of multidisciplinary therapies including immune checkpoint inhibitors for esophageal squamous cell carcinoma (ESCC) requires a clear understanding of immunological responses induced by chemotherapy with/without radiotherapy in the tumor microenvironment. PATIENTS AND METHODS: This is a retrospective analysis of paired pretreatment biopsy samples and surgically resected tumor samples of 49 patients who underwent radical surgery for ESCC with/without neoadjuvant therapy at Fukushima Medical University Hospital. The cohort included 30 patients treated with neoadjuvant chemotherapy (NAC), 11 treated with neoadjuvant chemoradiotherapy (NACRT), and eight who underwent surgery alone and did not receive neoadjuvant antitumor therapy. Chemotherapy included fluoropyrimidine- and platinum-based agents in all treated patients, and radiotherapy included 40 or 42 Gy administered in 20 or 21 fractions. Expression of CD8, human leukocyte antigen (HLA) class I-ABC, PD-L1, PD-L2, CEACAM-1, LSECtin, and p-STAT1, were determined using immunohistochemistry. RESULTS: The frequency of tumor-infiltrating CD8+ T cells was significantly increased by NAC (p<0.05), and the expression of HLA class I-ABC on tumor cells was significantly increased by NAC and NACRT (p<0.05). Furthermore, the ESCC cells expressed PD-L1, PD-L2, and CEACAM-1, whereas the expression of PD-L1 on ESCC cells was significantly correlated with the expression of p-STAT1 in ESCC cells (p<0.05). CONCLUSION: NAC and NACRT induced both positive and negative immunological responses in patients with ESCC. These results may be a part of basis for multidisciplinary therapy including immune checkpoint inhibitors for patients with advanced ESCC.
Assuntos
Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Humanos , Carcinoma de Células Escamosas do Esôfago/patologia , Terapia Neoadjuvante/métodos , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/patologia , Antígeno B7-H1/metabolismo , Linfócitos T CD8-Positivos , Estudos Retrospectivos , Microambiente Tumoral , Inibidores de Checkpoint Imunológico/farmacologia , PrognósticoRESUMO
BACKGROUND/AIM: The limited efficacy of immune checkpoint inhibitors in colorectal cancer (CRC) is likely due to immunosuppressive mechanisms including T cell exhaustion caused by inhibitory immune checkpoints in the tumor microenvironment. MATERIALS AND METHODS: We investigated the expression status of the inhibitory immune checkpoint receptors on tumor-infiltrating T cells and their ligands on tumor cells by flow cytometry and immunohistochemistry, using surgically-resected specimens of CRC. RESULTS: Flow cytometry analysis indicated that TIM-3, TIGIT, and PD-1 were expressed on tumor-infiltrating CD4+ (8.3%, 56.0%, 26.1%) and CD8+ T cells (8.2%, 51.6%, 23.5%), and CRC cells abundantly expressed PD-L1, CEACAM-1, and CD155 (2.2%, 77.0%, 46.8%). Immunohistochemical analysis revealed that the tumor proportional score of PD-L1, CEACAM-1, and CD155 was 42.4%, 54.2%, and 52.1%, respectively. CONCLUSION: PD-1, TIM-3, and TIGIT axes may reduce T cell function in the CRC tumor microenvironment.
Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias Colorretais/patologia , Proteínas de Checkpoint Imunológico/metabolismo , Linfócitos do Interstício Tumoral/imunologia , Receptores Imunológicos/metabolismo , Microambiente Tumoral/imunologia , Idoso , Idoso de 80 Anos ou mais , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/metabolismo , Feminino , Seguimentos , Humanos , Ligantes , Masculino , Pessoa de Meia-Idade , PrognósticoRESUMO
Trastuzumab deruxtecan (T-DXd), a HER2-targeting antibody-drug conjugate with a topoisomerase I inhibitor deruxtecan (DXd), exhibits an excellent anti-tumor effect in previously treated HER2-positive tumors. A recent study demonstrated that T-DXd not only suppressed tumor growth but also enhanced anti-tumor immunity through increasing the number of tumor-infiltrating CD8+ T cells and enhancement of major-histocompatibility-complex class I expression on tumor cells in a mouse model. However, the effect of T-DXd on anti-tumor immune responses in human cancers is largely unknown. We investigated the effect of T-DXd on the expression of HLA class I and CXCL9/10/11, T-cell chemoattractants, in HER2-positive human gastric cancer (GC) cells. We found that T-DXd significantly inhibited GC cell proliferation in a HER2-dependent manner, while it slightly increased the expression of HLA class I in HER2-positive GC cells. Moreover, we revealed that T-DXd significantly induced mRNA expression of CXCL9/10/11 in HER2-positive GC cells. T-DXd-triggered up-regulation of these chemokines was mediated through the activation of DNA damage signaling pathways. These results suggest that T-DXd triggers anti-tumor immune responses at least in part through induction of the expression of HLA class I and CXCL9/10/11 on HER2-positive GC cells, resulting in the enhancement of anti-tumor immunity in human GC.
Assuntos
Camptotecina/análogos & derivados , Quimiocina CXCL10/genética , Quimiocina CXCL11/genética , Quimiocina CXCL9/genética , Antígenos de Histocompatibilidade Classe I/metabolismo , Imunoconjugados/uso terapêutico , Receptor ErbB-2/metabolismo , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/imunologia , Trastuzumab/uso terapêutico , Camptotecina/farmacologia , Camptotecina/uso terapêutico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Quimiocina CXCL10/metabolismo , Quimiocina CXCL11/metabolismo , Quimiocina CXCL9/metabolismo , Fatores Quimiotáticos/farmacologia , Dano ao DNA , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Imunoconjugados/farmacologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Neoplasias Gástricas/genética , Trastuzumab/farmacologia , Regulação para Cima/efeitos dos fármacosRESUMO
The tumor microenvironment (TME) plays a key role in the efficacy of neoadjuvant chemotherapy (NAC) in solid tumors including esophageal squamous cell carcinoma (ESCC). However, the TME profile of ESCC treated with NAC is not fully understood. In this study, we investigated the effect of NAC on the TME especially tumor-associated macrophages (TAM), the important immunosuppressive components of the TME, in ESCC. We quantified the expression of CD163, a crucial marker of TAM, in pretherapeutic biopsy and surgically resected ESCC specimens from patients who received NAC (n = 33) or did not receive NAC (n = 12). We found that NAC dramatically increased the expression of CD163 on TAMs in ESCC. Colony-stimulating factor 1 (CSF-1) and IL34 are crucial cytokines that recruit monocytes into tumor sites and differentiate them into TAMs. Interestingly, NAC significantly upregulated the expression of IL34 but not CSF-1 on tumor cells, and the frequencies of CD163+ TAMs were significantly correlated with IL34 expression in ESCC after NAC. The expression of IL34 in NAC-nonresponsive patients was significantly higher than that in NAC-responsive patients, and patients with IL34-high ESCC exhibited worse prognosis as compared with patients with IL34-low ESCC. We also demonstrated that 5-fluorouracil (5-FU)/cisplatin preferentially increased mRNA expression of IL34 on human ESCC cell lines. Human peripheral blood monocytes co-cultured with ESCC cells treated with 5-FU/cisplatin increased the expression of CD163, which was attenuated by the treatment with CSF-1R inhibitors. These data suggest that IL34 expression by NAC shifts the TME toward CD163+ TAM-rich immunosuppressive and chemo-insensitive microenvironment in ESCC. IMPLICATIONS: The blockade of IL34 signaling may offer a novel therapeutic strategy against chemoresistance in ESCC by inhibiting M2-TAM polarization.