Peripheral T-cell repertoire alterations are common and affect outcome in large cell neuroendocrine lung carcinoma

 

Introduction:

Large cell neuroendocrine lung carcinoma (LCNEC) is a rare disease with poor prognosis and limited treatment options. Currently actionable genetic alterations are exceedingly uncommon in these patients, therefore alternative therapeutic approaches are urgently needed. Everolimus, an mTOR inhibitor with immunomodulatory and antiproliferative activity, in combination with carboplatin and paclitaxel proved a well-tolerated and effective first-line treatment for patients with metastatic LCNEC in the CRAD001KDE37 phase II trial. Immunologic parameters could be therapeutically relevant in this entity, but systematic studies are lacking.

Methods:

Blood samples from LCNEC patients of the CRAD001KDE37 trial at baseline (n = 35) and 3 months after beginning of treatment (n = 24) as well as from age-matched healthy current/ex-smokers (n = 11) and never-smokers (n = 10) were collected in PAXgene RNA tubes and analyzed by T-cell receptor (TCR) Vβ spectratyping (24 families). The Hamming distances (HD) for each Vβ family of each LCNEC patient and current/ex-smoker were calculated with reference to the average distributions in the never-smoker group and compared using a mixed linear model in SPSS with group as a fixed and Vβ family as a random effect.

Results:

The TCR Vβ repertoire was skewed in untreated LCNEC patients compared to that of current/ex-smokers [mean average HD across Vβ families (HDa) 0.21 vs. 0.17, p < 0.001]. The baseline lymphocyte counts and HDa values of LCNEC patients correlated strongly (ρ= 0.49, p = 0.003) and were both significantly higher in the 15/35 cases with a tumor response at month 3 (1.8 vs. 1.3/nl, p = 0.044, and 0.22 vs. 0.18, p = 0.018 respectively). At 3 months, the T-cell repertoire of LCNEC patients still showed significant alterations (mean HDa = 0.20, p < 0.001 compared to the group of current/ex-smokers), which correlated with the changes at baseline (p < 0.001). Patients with a higher degree of repertoire normalization at 3 months (i.e. an above-average reduction of HDa) had a significantly better overall survival (617 vs. 316 days, p = 0.036).

Conclusions:

Immunologic changes are important for the natural history and treatment response in LCNEC. Their better understanding could guide immunomodulatory strategies and help improve patient outcome in this orphan disease.