Mutually exclusive expression of CD73 and PDL1 in tumors from patients (pt) with NSCLC, gastroesophageal (GE) and urothelial bladder carcinoma (UBC).

Abstract

3079 Background: Tumors use multiple means of immune evasion, notably the programmed death-1 (PD1)/PDL1 pathway. Anti-PD1/PDL1 therapy induces anti-tumor activity and has improved pt outcomes. Activation of the immunosuppressive CD39/CD73/adenosine pathway might play a role in pts who do not benefit from anti-PD1/PDL1 therapies. We evaluated expression of CD73 and PDL1 and explored the association between CD73 and intraepithelial (IE) CD8+ cells (TILs) to begin to understand their potential interplay in cancer. Methods: Immunohistochemistry for PDL1, CD73 and CD8 was conducted on tumors of non-squamous NSCLC (NSq) (n=42), GE (n=50), and UBC (n=50). PDL1 and CD73 were scored by image analysis with Definiens software. IE CD8+ TILs were scored semi-quantitatively by a pathologist (0-2 = low; 3-4 = high). Using the top tertile of PDL1 and CD73 for high expression levels, a Fisher’s meta-analysis was calculated across the three indications. Results: Across all tumors, 25% (35/142) were PDL1 high (+), but CD73 low (-) and another 25% (35/142) were CD73+ but PDL1- (p=0.06, see table). This trend for mutually exclusive high expression of PDL1/CD73 was strongest in GE (p<0.01). In the PDL1+ group 76% (35/46) had high IE CD8+ TILs whereas in the CD73+ group only 35% (16/46) had high TILs (p<0.0001 using a proportions test). In the PDL1+/CD73- pt subset 77% (27/35) were CD8+ high vs only 23% (8/35) in the PDL1-/CD73+ subset. Conclusions: The identification of distinct pt subsets based on high PDL1 and/or CD73 expression suggests that tumors have multiple mechanisms of immune evasion. Increased IE CD8+ TILs were associated with PDL1 expression. The finding that PDL1-/ CD73+ tumors have lower IE CD8+ TILs compared to PDL1+/CD73- tumors suggests a role for CD73 in excluding IE TILs. Larger sample sets are needed to confirm these findings and to further explore any relationship with the tumor microenvironment. Our data suggests potential approaches to identify subsets of pts likely to benefit from immunotherapy targeting PDL1 and CD73. [Table: see text]

Clinical and Molecular Characteristics Associated With Survival Among Patients Treated With Checkpoint Inhibitors for Advanced Non–Small Cell Lung Carcinoma

“…Other recent insights that may help to further elucidate the mechanisms of resistance include the finding that EGFR mutant tumors are associated with a high frequency of inactive tumor-infiltrating lymphocytes even though lymphocytes are present in the tumor microenvironment. 19 The finding that high CD73 expression on NSCLC and other tumors is associated with low PD-L1 expression and low densities of CD8 + tumor-infiltrating lymphocytes 20 may also provide an explanation given that EGFR activation is thought to induce CD73 expression. One hypothesis raised is that in the EGFR mutant tumors with overexpression of CD73, which is also associated with reduced expression of interferon gamma messenger RNA signature, 21 CD73 results in immunosuppression via decreased T-cell activation and effector function and hence reduced benefit from checkpoint inhibitor therapies.…”

Immune-checkpoint inhibitor plus chemotherapy versus conventional chemotherapy for first-line treatment in advanced non-small cell lung carcinoma: a systematic review and meta-analysis

“…Typically, patients with EGFR or ALK genomic alterations receive little OS advantage with the single agent PD-1/PD-L1 inhibitor [34]. Despite the high PD-L1 expression in oncogene-addicted tumors [35, 36], they are associated with a high frequency of inactive tumor-infiltrating lymphocytes [37], low mutation load [38], and weak immunogenicity [39]. These factors are hypothesized to account for the inferior efficacy of immunotherapy in patients with EGFR - or ALK -driven NSCLC.…”

Landscape of adenosine pathway and immune checkpoint dual blockade in NSCLC: progress in basic research and clinical application

“…CD73 expression has been found to be positively correlated with histopathological grade, tumor invasion, and lymph node metastasis ( 63 , 89 ). Of particular interest is the correlation between CD73 and PD-1/PD-L1 expression ( 63 , 90 , 91 ). The expression of both PD-L1 and CD73 is elevated in drug-resistant NSCLC following treatment with EGFR-TKIs ( 53 ).…”