Killing SCLC: insights into how to target a shapeshifting tumor

Abstract

Small cell lung cancer (SCLC) is a rapidly growing, highly metastatic, and relatively immune-cold lung cancer subtype. Historically viewed in the laboratory and clinic as a single disease, new discoveries suggest that SCLC comprises multiple molecular subsets. Expression of MYC family members and lineage-related transcription factors ASCL1, NEUROD1, and POU2F3 (and, in some studies, YAP1) define unique molecular states that have been associated with distinct responses to a variety of therapies. However, SCLC tumors exhibit a high degree of intratumoral heterogeneity, with recent studies suggesting the existence of tumor cell plasticity and phenotypic switching between subtype states. While SCLC plasticity is correlated with, and likely drives, therapeutic resistance, the mechanisms underlying this plasticity are still largely unknown. Subtype states are also associated with immune-related gene expression, which likely impacts response to immune checkpoint blockade and may reveal novel targets for alternative immunotherapeutic approaches. In this review, we synthesize recent discoveries on the mechanisms of SCLC plasticity and how these processes may impinge on antitumor immunity.

Keywords: heterogeneity; lung cancer; neuroendocrine; plasticity; small cell.

Figure 1.

Basic clinical background on small cell lung cancer (SCLC) (in the text box; left) with illustrated sites of metastatic spread (right).

Figure 2.

Intratumoral heterogeneity and mechanisms of plasticity in SCLC. (Left) SCLC cells within individual human tumors are classified as NE-high (SCLC-A and SCLC-N subtypes) or non-NE SCLC (SCLC-Y and SCLC-P subtypes). Non-NE tumor cells are immunomodulatory and have an increased response to immune checkpoint blockade (ICB). (Top right) SCLC cells demonstrate subtype plasticity. SCLC-A cells can evolve to SCLC-N and SCLC-Y. It remains unknown whether (1) SCLC-P can evolve to or from the other subtypes or (2) non-NE cells can convert back to a NE-high phenotype. (Middle right) Molecular mechanisms implicated in driving NE to non-NE SCLC cell fate transition.

Figure 3.

SCLC transcriptional subtypes display distinct immunogenic profiles that may impact response to immune checkpoint blockade (ICB). (NE) Neuroendocrine, (non-NE) nonneuroendocrine. The yellow arrow reflects potential enhanced responsiveness of the SCLC-Y/I subtypes to ICB, while SCLC-N has been suggested to be the most immune-cold.