Compartmental Analysis of T-cell Clonal Dynamics as a Function of Pathologic Response to Neoadjuvant PD-1 Blockade in Resectable Non–Small Cell Lung Cancer

Abstract

Purpose: Neoadjuvant PD-1 blockade is a promising treatment for resectable non-small cell lung cancer (NSCLC), yet immunologic mechanisms contributing to tumor regression and biomarkers of response are unknown. Using paired tumor/blood samples from a phase II clinical trial (NCT02259621), we explored whether the peripheral T-cell clonotypic dynamics can serve as a biomarker for response to neoadjuvant PD-1 blockade. Experimental Design: T-cell receptor (TCR) sequencing was performed on serial peripheral blood, tumor, and normal lung samples from resectable NSCLC patients treated with neoadjuvant PD-1 blockade. We explored the temporal dynamics of the T-cell repertoire in the peripheral and tumoral compartments in response to neoadjuvant PD-1 blockade by using the TCR as a molecular barcode. Results: Higher intratumoral TCR clonality was associated with reduced percent residual tumor at the time of surgery, and the TCR repertoire of tumors with major pathologic response (MPR; <10% residual tumor after neoadjuvant therapy) had a higher clonality and greater sharing of tumor-infiltrating clonotypes with the peripheral blood relative to tumors without MPR. Additionally, the posttreatment tumor bed of patients with MPR was enriched with T-cell clones that had peripherally expanded between weeks 2 and 4 after anti-PD-1 initiation and the intratumoral space occupied by these clonotypes was inversely correlated with percent residual tumor. Conclusions: Our study suggests that exchange of T-cell clones between tumor and blood represents a key correlate of pathologic response to neoadjuvant immunotherapy and shows that the periphery may be a previously underappreciated originating compartment for effective antitumor immunity. See related commentary by XXX, p. XXX

Molecular T-Cell Repertoire Analysis as Source of Prognostic and Predictive Biomarkers for Checkpoint Blockade Immunotherapy

“…On the contrary, non-responder tumors did not successfully traffic top 1% intratumor clonotypes to the tumor bed, possibly due to an intrinsically more exhausted, less migratory T cell repertoire. This phenomenon supports the idea that the formation of T-cell clones committed against the tumor can expand to other tissues in order to fight micrometastasis, thereby providing a justification for the use of immune checkpoint inhibitors prior to surgery [75,98].…”

“…The continuation of this study presented a more exhaustive characterization of the dynamics of the repertoire in relation to neoadjuvant PD-1 blockade [98]. Tumor clonality positively correlated with tumor mutational burden, and inversely associated with residual tumors, thus supporting the hypothesis that a high tumor mutational burden increases the likelihood that neoantigens can drive a clonally skewed intratumor T cell repertoire leading to tumor pathological regression.…”

The Promises and Challenges of Tumor Mutation Burden as an Immunotherapy Biomarker: A Perspective from the International Association for the Study of Lung Cancer Pathology Committee

“…94 In NSCLC treated with ICI, emerging data also suggest an association of higher intratumoral TCR clonality with better outcome at a metastatic stage and a reduced percentage of residual tumor in a neoadjuvant PD-1 setting. 95,96 TCR clonality and diversity in the peripheral blood of patients with NSCLC may also serve as noninvasive predictors of response to ICI. 96,97 A higher TCR diversity index in EGFR-mutated than EGFR wild-type tumors might suggest a higher Tcell clonal expansion in EGFR wild-type tumors.…”

“…95,96 TCR clonality and diversity in the peripheral blood of patients with NSCLC may also serve as noninvasive predictors of response to ICI. 96,97 A higher TCR diversity index in EGFR-mutated than EGFR wild-type tumors might suggest a higher Tcell clonal expansion in EGFR wild-type tumors. 98 This could indirectly point to a possible reason for the unfavorable response of EGFR-mutated NSCLC to ICI.…”

Tumor Infiltrating Effector Memory Antigen-Specific CD8+ T Cells Predict Response to Immune Checkpoint Therapy

“…ICT drives dynamic changes in CTL frequency (7,9), phenotype (10)(11)(12), proliferation (13,14), and cytotoxic function (6,15). T cell receptor (TCR) sequencing studies further suggest that ICT causes clonal proliferation of CTLs within the tumor (7,16,17) and the periphery (16,18,19). As antigen-specificity is crucial for a successful anti-tumor response, we reasoned that dynamic changes in tumor antigen-specific CTLs could inform ICT responses.…”