Cold and heterogeneous T cell repertoire is associated with copy number aberrations and loss of immune genes in small-cell lung cancer

Abstract

Small-cell lung cancer (SCLC) is speculated to harbor complex genomic intratumor heterogeneity (ITH) associated with high recurrence rate and suboptimal response to immunotherapy. Here, using multi-region whole exome/T cell receptor (TCR) sequencing as well as immunohistochemistry, we reveal a rather homogeneous mutational landscape but extremely cold and heterogeneous TCR repertoire in limited-stage SCLC tumors (LS-SCLCs). Compared to localized non-small cell lung cancers, LS-SCLCs have similar predicted neoantigen burden and genomic ITH, but significantly colder and more heterogeneous TCR repertoire associated with higher chromosomal copy number aberration (CNA) burden. Furthermore, copy number loss of IFN-γ pathway genes is frequently observed and positively correlates with CNA burden. Higher mutational burden, higher T cell infiltration and positive PD-L1 expression are associated with longer overall survival (OS), while higher CNA burden is associated with shorter OS in patients with LS-SCLC.

A 2022 Update on Extensive Stage Small-Cell Lung Cancer (SCLC)

“…In the absence of essential knowledge about the main molecular mechanisms, which underlie escape from immune surveillance, tumor progression and chemoresistance, it is difficult to "crack the code" of SCLC and to design rational treatment strategies for it. The major causes of this knowledge gap are 1) the small sample size of SCLC relative to NSCLC, which makes it more challenging to test new treatments in randomized clinical trials and 2) the paucity of adequate tumor specimens to guide rational drug design as surgery is rarely used to treat extensive stage SCLC [60], which at diagnosis is almost always disseminated. Also, biopsy in the setting of disease relapse is a major challenge, although liquid biopsies enriched from a standard peripheral blood draw may offer a repeatable alternative since circulating tumor cells are abundant in SCLC.…”

Lung Fibroblasts from Idiopathic Pulmonary Fibrosis Patients Harbor Short and Unstable Telomeres Leading to Chromosomal Instability

“…Moreover, control fibroblasts were obtained from normal lung tissue during surgery for lung cancer in smokers, and we cannot rule out the possibility that telomere length and chromosomal abnormalities may have been affected by this pre-malignant environment. Previously, studies on lung tumors and peripheral blood lymphocytes from the same patients demonstrate a prospective correlation between chromosomal instability detected in peripheral blood lymphocytes and lung cancer in smokers suggesting that chromosomal alterations detected in lymphocytes reflect chromosomal damage and tumor initiation in other tissues such as the lung [ 48 , 49 ]. In addition, the role of smoking in the formation of DNA damage and persistent local inflammation has been described [ 50 ].…”

Killing SCLC: insights into how to target a shapeshifting tumor

“…Given that Notch receptor genes and many epigenetic regulators are genomically altered in SCLC, it would be valuable to determine how these genomic alterations impact plasticity and whether they are predictive of therapeutic responses. Moreover, recent studies that have reconstructed the phylogenetics of SCLC revealed that the majority of somatic alterations (∼80%) represent “trunk” mutations ( Chen et al 2021b ; Zhou et al 2021 ). It remains unknown whether these alterations could serve as useful neoantigens for immunotherapeutic purposes ( Levine et al 2019 ).…”