Immune landscape in vulvar cancer-draining lymph nodes indicates distinct immune escape mechanisms in support of metastatic spread and growth

• Published in: Journal for immunotherapy of cancer 2021-10, Vol.9 (10), p.e003623
• Main Authors: Heeren, Anne Marijne, Rotman, Jossie, Samuels, Sanne, Zijlmans, Henry J M A A, Fons, Guus, van de Vijver, Koen K, Bleeker, Maaike C G, Kenter, Gemma G, Jordanova, Ekaterina J, de Gruijl, Tanja D
• Format: Article
• Language: English
• Subjects: Adult; Aged; Basic Tumor Immunology; Cancer; Cancer therapies; cytokines; Cytotoxicity; Decision making; dendritic cells; Female; Flow cytometry; Genital cancers; Human papillomavirus; Humans; Immunotherapy; Lymph Nodes - pathology; Lymphatic Metastasis - immunology; Lymphatic system; Lymphocytes; Metastasis; Middle Aged; myeloid-derived suppressor cells; Neoplasm Metastasis; Pathology; Patients; Surgery; T-lymphocytes; Transcription factors; Tumor Microenvironment; Tumors; Vulvar Neoplasms - immunology
• ISSN: 2051-1426; 2051-1426
• DOI: 10.1136/jitc-2021-003623

BackgroundTherapeutic immune intervention is highly dependent on the T-cell priming and boosting capacity of tumor-draining lymph nodes (TDLN). In vulvar cancer, in-depth studies on the immune status of (pre)metastatic TDLN is lacking.MethodsWe have phenotyped and enumerated various T-cell and myeloid subsets in tumor-free (LN−, n=27) and metastatic TDLN (LN+, n=11) using flow cytometry. Additionally, we studied chemokine and cytokine release profiles and assessed expression of indoleamine 2,3-dioxygenase (IDO) in relation to plasmacytoid dendritic cell (pDC) or myeloid subsets.ResultsMetastatic involvement of TDLN was accompanied by an inflamed microenvironment with immune suppressive features, marked by hampered activation of migratory DC, increased cytokine/chemokine release, and closely correlated elevations of pDC and LN-resident conventional DC (LNR-cDC) activation state and frequencies, as well as of terminal CD8+ effector-memory T-cell (TemRA) differentiation, regulatory T-cell (Treg) rates, T-cell activation, and expression of cytotoxic T-lymphocyte protein-4 (CTLA-4) and programmed cell death protein-1 (PD-1) immune checkpoints. In addition, high indoleamine 2,3-dioxygenase (IDO) expression and increased frequencies of monocytic myeloid-derived suppressor cells (mMDSC) were observed. Correlation analyses with primary and metastatic tumor burden suggested respective roles for Tregs and suppression of inducible T cell costimulator (ICOS)+ T helper cells in early metastatic niche formation and for CD14+ LNR-cDC and terminal T-cell differentiation in later stages of metastatic growth.ConclusionsMetastatic spread in vulvar TDLN is marked by an inflamed microenvironment with activated effector T cells, which are likely kept in check by an interplay of suppressive feedback mechanisms. Our data support (neoadjuvant) TDLN-targeted therapeutic interventions based on CTLA-4 and PD-1 blockade, to reinvigorate memory T cells and curb early metastatic spread and growth.