TY - JOUR
T1 - Lymphovascular Invasion Is Associated With Mutational Burden and PD-L1 in Resected Lung Cancer
AU - Mitchell, Kyle G.
AU - Negrao, Marcelo V.
AU - Parra, Edwin R.
AU - Li, Jun
AU - Zhang, Jianhua
AU - Dejima, Hitoshi
AU - Vaporciyan, Ara A.
AU - Swisher, Stephen G.
AU - Weissferdt, Annikka
AU - Antonoff, Mara B.
AU - Cascone, Tina
AU - Roarty, Emily
AU - Wistuba, Ignacio I.
AU - Heymach, John V.
AU - Gibbons, Don L.
AU - Zhang, Jianjun
AU - Sepesi, Boris
N1 - Funding Information:
In the present study of chemotherapy-naïve, surgically resected lung cancers we observed lower TMB and tumor expression of PD-L1 compared with previously published values for metastatic NSCLC. 2 , 17 We also identified differential TMB and expression of PD-L1 that varied according to baseline patient and pathologic tumor characteristics. These findings have potential clinical relevance, as future clinical trials utilizing checkpoint inhibitor immunotherapy could explore the presence of LVI, in addition to TMB and PD-L1, as a patient stratification or selection criterion. As immune checkpoint inhibitors continue to be explored in the setting of early NSCLC, an ability to identify patient subgroups most likely to derive therapeutic benefit from these agents is greatly needed. 9 , 10 Outside of induction clinical trials, the majority of surgically resectable NSCLC patients undergo resection of the primary tumor and mediastinal lymph nodes first, with further decisions about additional therapy guided by the final pathology. 8 In patients with metastatic disease, a TMB greater than 10 mut/Mb has been identified as predictive of response to checkpoint blockade. 8 The contrast between the frequency of tumors with TMB in excess of that threshold in the present report (22%) and that published in CheckMate 277 (44%) highlights the need for exploration of additional features that can be used singly or in combination to predict therapeutic benefit in patients with resectable disease. 8 We submit that our observation that the presence of LVI in the final pathologic specimen is associated with increased TMB and PD-L1 could potentially serve as a guide for the type of adjuvant therapy in NSCLC patients after resection, as assessment of LVI is routinely performed at the time of pathologic evaluation. Tumors that demonstrate LVI have a high propensity for distant recurrence, even if resected in very early stages. 18 However, current guidelines for adjuvant chemotherapy are based on the tumor size and nodal status rather than the presence or absence of LVI or high TMB and PD-L1. 8 Additionally, the ANVIL trial (NCT02595944) of adjuvant nivolumab does not further stratify patients who meet the inclusion criteria of absent EGFR mutations or ALK rearrangements. As we try to identify patients at increased risk of recurrence after complete surgical resection of early lung cancers, and as we search for more effective and safe adjuvant therapies, we speculate that patients with high TMB, PD-L1, and LVI may derive a therapeutic benefit from adjuvant anti-PD-1/PD-L1 agents, either as monotherapy or in combination with chemotherapy. The identification of higher tumor infiltration by cytotoxic T lymphocytes, B lymphocytes, and macrophages expressing PD-L1 among tumors with higher TMB and expression of PD-L1 further supports this interpretation, because the efficacy of checkpoint blockade is greatest in the setting of concurrent high checkpoint expression and effector/helper lymphocyte infiltration. 19 , 20 Tumor PD-L1 expression has been identified as being associated with increased densities of immune infiltrates, and checkpoint inhibitor-induced release of PD-1 + T lymphocytes from immune cells expressing PD-L1 has been postulated as another mechanism by which antitumor immunity is enhanced by these agents. 20-23 The role of B lymphocytes in the microenvironment has not been fully characterized, but recent work has demonstrated that they play important roles in antigen presentation and elaboration of antitumor antibodies and have protective prognostic effects. 24 It seems plausible that the group of patients with tumors characterized by high TMB, elevated PD-L1 expression, the presence of LVI, and higher tumor immune cell infiltration would be that which is best suited for novel adjuvant immunotherapy trials in early NSCLC. On the other hand, for patients with a predicted poor anti-tumor immune response, the preferred strategy may employ a combination of anti-PD-1/PD-L1 agents with CTLA-4 blockade or chemotherapy in an effort to improve lymphocyte recruitment. 25 Despite the strength provided by the prospective nature of our study, we must acknowledge its limitations. Because only a subset of the tumors in the ICON project had both multiplex immunofluorescence and TMB data available for analysis, the present study is limited by its small sample size and lack of a validation set. Although the methodology of analysis of cell densities in this study (ie, multiplex immunofluorescence) differs from that used to quantify PD-L1 expression clinically (ie, tumor proportion score), multiplex immunofluorescence permits precise quantification of cell densities and has been previously validated in comparison with chromogenic immunohistochemistry. 12 Moreover, the presence of LVI is not reliably detected on preoperative biopsy, and the applicability of these findings may be limited to the adjuvant setting after complete pathological assessment of the surgical specimen. Additionally, the short follow-up in this cohort and few observed RFS events to date precluded a robust analysis of the relationships between tumor microenvironment features with prognostic outcomes while controlling for relevant clinicopathologic characteristics. Further analyses of the prognostic impact of these features will be performed as follow-up data in this cohort matures. In summary, we report that primary NSCLC tumors with synchronous elevated TMB and PD-L1 expression are associated with the presence of LVI and with enhanced intratumoral immune cell infiltration. Further study is warranted to examine whether these findings can improve patient selection for novel trials of immune checkpoint inhibitor therapy in the adjuvant setting. The authors appreciate the contributions of the University of Texas MD Anderson ICON team. This work has been supported by generous philanthropic support of the University of Texas MD Anderson Moon Shot GEMINI Project, Lung SPORE P50CA070907 , CCSG P30CA016672 . Dr Gibbons has received research funding from AstraZeneca , Janssen, and Takeda. Dr Heymach has received research support from AstraZeneca , Bayer , GlaxoSmithKline , and Spectrum . Dr Cascone has received research funding to MD Anderson Cancer Center from Boehringer Ingelheim and Bristol-Myers Squibb .
Funding Information:
The authors appreciate the contributions of the University of Texas MD Anderson ICON team. This work has been supported by generous philanthropic support of the University of Texas MD Anderson Moon Shot GEMINI Project, Lung SPORE P50CA070907, CCSG P30CA016672. Dr Gibbons has received research funding from AstraZeneca, Janssen, and Takeda. Dr Heymach has received research support from AstraZeneca, Bayer, GlaxoSmithKline, and Spectrum. Dr Cascone has received research funding to MD Anderson Cancer Center from Boehringer Ingelheim and Bristol-Myers Squibb.
Publisher Copyright:
© 2020 The Society of Thoracic Surgeons
PY - 2020/2
Y1 - 2020/2
N2 - Background: High tumor mutational burden (TMB) and programmed death ligand 1 (PD-L1) expression are leading biomarkers in metastatic non-small cell lung cancer (NSCLC) and predict favorable response to checkpoint inhibitors. We sought to identify clinicopathologic characteristics associated with elevated TMB and PD-L1 expression among patients who underwent resection for NSCLC. Methods: NSCLC patients undergoing primary resection (2016-2018) were prospectively enrolled in an immunogenomic profiling project. Multiplex immunofluorescence quantified densities (cells/mm2) of CD3+, CD3+CD8+, CD3+CD8+PD-1+, malignant cells (MCs), MCsPD-L1+, CD68+, CD68+PD-L1+, and CD20+ cells. Whole-exome sequencing quantified TMB (mutations/megabase). TMB and MCsPD-L1+ were dichotomized according to the median of each. Results: A total of 55 patients completed multiplex immunofluorescence and whole-exome sequencing profiling. In this sample, 41.8% (23 of 55) had pathologic stage I disease. Median TMB and MCsPD-L1+ were 3.91 and 0.62 cells/mm2, respectively. TMB was higher among smokers (P =.001) and tumors with lymphovascular invasion (LVI) (P =.051). TMB was positively correlated with densities of MCsPD-L1+ (r = 0.293, P =.030), CD68+PD-L1+ (r = 0.289, P =.033), and CD20+ (r = 0.310, P =.043) cells. The density of MCsPD-L1+ was associated with increased CD3+CD8+ (r = 0.319, P =.018) and CD68+PD-L1+ (r = 0.371, P =.005) cells. Patients with PD-L1HighTMBHigh tumors (30.9%, 17 of 55) had higher intratumoral densities of CD3+, CD3+CD8+, CD68+, CD68+PD-L1+, and CD20+ cells. On multivariable analysis LVI was associated with synchronous elevated TMB and PD-L1 expression (odds ratio 3.53, P =.039). Conclusions: NSCLC tumors with elevated TMB and PD-L1 expression are associated with LVI and increased intratumoral immune cell infiltration. These findings may potentially improve patient selection for checkpoint inhibitor therapy trials in the adjuvant setting.
AB - Background: High tumor mutational burden (TMB) and programmed death ligand 1 (PD-L1) expression are leading biomarkers in metastatic non-small cell lung cancer (NSCLC) and predict favorable response to checkpoint inhibitors. We sought to identify clinicopathologic characteristics associated with elevated TMB and PD-L1 expression among patients who underwent resection for NSCLC. Methods: NSCLC patients undergoing primary resection (2016-2018) were prospectively enrolled in an immunogenomic profiling project. Multiplex immunofluorescence quantified densities (cells/mm2) of CD3+, CD3+CD8+, CD3+CD8+PD-1+, malignant cells (MCs), MCsPD-L1+, CD68+, CD68+PD-L1+, and CD20+ cells. Whole-exome sequencing quantified TMB (mutations/megabase). TMB and MCsPD-L1+ were dichotomized according to the median of each. Results: A total of 55 patients completed multiplex immunofluorescence and whole-exome sequencing profiling. In this sample, 41.8% (23 of 55) had pathologic stage I disease. Median TMB and MCsPD-L1+ were 3.91 and 0.62 cells/mm2, respectively. TMB was higher among smokers (P =.001) and tumors with lymphovascular invasion (LVI) (P =.051). TMB was positively correlated with densities of MCsPD-L1+ (r = 0.293, P =.030), CD68+PD-L1+ (r = 0.289, P =.033), and CD20+ (r = 0.310, P =.043) cells. The density of MCsPD-L1+ was associated with increased CD3+CD8+ (r = 0.319, P =.018) and CD68+PD-L1+ (r = 0.371, P =.005) cells. Patients with PD-L1HighTMBHigh tumors (30.9%, 17 of 55) had higher intratumoral densities of CD3+, CD3+CD8+, CD68+, CD68+PD-L1+, and CD20+ cells. On multivariable analysis LVI was associated with synchronous elevated TMB and PD-L1 expression (odds ratio 3.53, P =.039). Conclusions: NSCLC tumors with elevated TMB and PD-L1 expression are associated with LVI and increased intratumoral immune cell infiltration. These findings may potentially improve patient selection for checkpoint inhibitor therapy trials in the adjuvant setting.
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U2 - 10.1016/j.athoracsur.2019.08.029
DO - 10.1016/j.athoracsur.2019.08.029
M3 - Article
C2 - 31550464
AN - SCOPUS:85078395238
SN - 0003-4975
VL - 109
SP - 358
EP - 366
JO - Annals of Thoracic Surgery
JF - Annals of Thoracic Surgery
IS - 2
ER -