NACT-mediated adjuvanticity positively impacts clinically relevant TLS maturation in metastatic HGSOC. A, Representative image of immunofluorescence of CD4, CD8, CD20, CD21, CD23, DC-LAMP, and GZMB staining (immunofluorescence panel 1). Scale bars, 10, 100 and 500 µm. B and C, Distribution of early TLS (eTLS; B) and mature TLS (mTLS; C) across pTME and mTME HGSOC tumor samples with/without NACT. Statistical significance was calculated by two-sided Mann–Whitney test. P values are indicated. D, Supervised hierarchical clustering of TLS-relevant gene signature (CCL2, CCL3, CCL4, CCL5, CCL8, CCL18, CCL19, CCL21, CXCL9, CXCL10, CXCL11, and CXCL13) across pTME and mTME HGSOC tumor samples with/without NACT. E and F, Overall survival (OS) of 60 (E) and 40 chemo-naïve and treated patients with mHGSOC (F), respectively (study cohort 1 and 2) based on median stratification of total mTLS. Survival curves were estimated by the Kaplan–Meier method, and differences between groups were evaluated using log-rank test. Number of patients at risk and P values are reported. G, Number of mTLS across patients with CALRLo and CALRHi mHGSOC with/without NACT as determined by median stratification. Mean and SEM are shown. Statistical significance was calculated by two-sided Mann–Whitney test. P values are indicated. H and I, OS of 60 and 40 patients with chemo-naïve and treated mHGSOC (study cohorts 1 and 2), upon stratification based on median frequency of mTLS and expression of CALR. Survival curves were estimated by the Kaplan–Meier method, and differences between groups were evaluated using the log-rank test.
ARTICLE ABSTRACT
Patients with high-grade serous ovarian carcinoma (HGSOC) are virtually insensitive to immune checkpoint inhibitors (ICI) employed as standalone therapeutics, at least in part reflecting microenvironmental immunosuppression. Thus, conventional chemotherapeutics and targeted anticancer agents that not only mediate cytotoxic effects but also promote the recruitment of immune effector cells to the HGSOC microenvironment stand out as promising combinatorial partners for ICIs in this oncological indication.
We harnessed a variety of transcriptomic, spatial, and functional assays to characterize the differential impact of neoadjuvant paclitaxel-carboplatin on the immunological configuration of paired primary and metastatic HGSOC biopsies as compared to neoadjuvant chemotherapy (NACT)-naïve HGSOC samples from five independent patient cohorts.
We found NACT-driven endoplasmic reticulum stress and calreticulin exposure in metastatic HGSOC lesions culminates with the establishment of a dense immune infiltrate including follicular T cells (TFH cells), a prerequisite for mature tertiary lymphoid structure (TLS) formation. In this context, TLS maturation was associated with an increased intratumoral density of ICI-sensitive TCF1+PD1+ CD8+ T cells over their ICI-insensitive TIM-3+PD1+ counterparts. Consistent with this notion, chemotherapy coupled with a PD1-targeting ICI provided a significant survival benefit over either therapeutic approach in syngeneic models of HGSOC bearing high (but not low) tumor mutational burden.
Altogether, our findings suggest that NACT promotes TLS formation and maturation in HGSOC lesions, de facto preserving an intratumoral ICI-sensitive T-cell phenotype. These observations emphasize the role of rational design, especially relative to the administration schedule, for clinical trials testing chemotherapy plus ICIs in patients with HGSOC.See related commentary by Bravo Melgar and Laoui, p. 10
