Commentary: understanding acquired resistance to immunotherapy in non-small cell lung cancer

INTRODUCTION

The therapeutic portfolio for non-small cell lung cancer (NSCLC) has undergone a significant transformation, driven by the remarkable progress in understanding immune checkpoint inhibitors (ICIs). It proposes substantial treatment options; however, due to acquired resistance (AR) from tumors, the long-term efficacy of these inhibitors has been limited, presenting a considerable hurdle in treatment. AR occurs when therapy imposes a selective pressure, driving tumor evolution through the expansion of resistant clones. These clones can use genetic, epigenetic, and/or adaptive mechanisms to bypass therapeutic effects, ultimately leading to disease progression, as illustrated in Figure 1. The clinical trajectories and molecular alterations discussed in these phenomena have been underlined in a recent article in Cancer Cell, “Clinical and molecular features of acquired resistance to immunotherapy in non-small cell lung cancer”^[1]. This study features a large scale of clinical data with comprehensive genomic analysis to understand the inclusive pattern of AR. The authors have emphasized that the complicated nature of immune evasion is achieved through the determination of several mechanisms of resistance, such as the loss of antigen presentation, upregulation of immune checkpoints, and remodeling of the tumor microenvironment (TME). Understanding these phenomena not only enhances the systematic comprehension of the tumor but also facilitates the dynamic monitoring of several biomarkers^[2].

Figure 1. Mechanism of Action of Immune Checkpoint Inhibition. Immune checkpoint inhibitors (e.g., anti-PD-1/PD-L1 antibodies) block the interaction between PD-1 on T cells and PD-L1 on tumor cells. This prevents the T cell inhibitory signal, allowing the activated T cell to recognize and attack the tumor cell via the T-cell receptor (TCR) and MHC-I interaction. The figure created with BioRender.com. PD-L1: Programmed cell death protein ligand 1; PD-1: programmed cell death protein 1; MHC-I: major histocompatibility complex class I.

FINDINGS OF THE ARTICLE

The analysis includes a cohort of 1,201 NSCLC patients treated with programmed cell death protein ligand 1 (PD-L1) blockade to explore the patterns of AR. Initially, all of the tumors responded to the immunotherapy; however, more than 60% of the patients developed resistance later, with half of them acquiring it within one year. These are alarming dynamics that require careful attention and timely action^[5]. The AR to ICIs is the reciprocal of both intrinsic and extrinsic tumor mechanisms. The intrinsic tumor mechanism is driven by alterations in the pathways of antigen presentation, disruption of interferon signaling, as well as alterations in pathways of oncogenic signaling, leading to reduced immunogenicity of the tumor. On the other hand, the extrinsic tumor mechanism is triggered by the immune microenvironment due to low CD8+ tumor-infiltrating lymphocytes (TIL) density and reduced programmed cell death protein 1 (PD-1)/PD-L1 activity, or an altered cytokine profile that affects antitumor immunity^[6], as shown in Table 1.

The comparison of the survival analysis suggested that the duration of survival for patients with AR is prolonged compared to those with primary resistance, highlighting the heterogeneity of resistance phenotypes and their prognostic significance. The study also analyzed the molecular interrogations of patients who had AR. Exome sequencing and whole transcriptome analysis were performed on 42 tumor samples from 29 patients (Microarray data) and 34 samples from 22 patients (whole exome sequencing), revealing that pivotal alterations in immune-related pathways trigger the resistance mechanism.

The key finding of this study is the identification of two molecular subsets in resistant tumors based on the expression of genes involved in interferon γ (IFNγ) signaling. The IFNγ response genes were upregulated in approximately 50% of the samples, while the remaining samples maintained stable expression levels. Interestingly, the subset, despite being upregulated by IFNγ, displayed defective interferon signaling marked by diminished downstream activity. This deviating IFNγ pathway activity demonstrates a complex interplay where high IFNγ exposure, primarily vital for antitumor immunity, can nurture immune escape through adaptive tumor rewiring.

Additional molecular profiling suggested mutations and heterozygosity loss in the components of antigen presentation machinery, including Beta-2 Microglobulin (B2M), mainly in the IFNγ-upregulated tumors, which may contribute to diminishing the antigen visibility of the tumor and avoiding recognition by cytotoxic T cells despite ongoing activation signals. The defective interferon signaling, along with the disruption in antigen presentation, reveals a complex resistance mechanism that evolves through a process of immune escape, whereby immunotherapy selectively promotes the outgrowth of resistant tumor clones^[12]. Crucially, these molecular insights were validated in murine models, where tumor cells exhibited AR to in vitro IFNγ stimulation following immune checkpoint blockade, summarizing the main features of observed resistance in patients. These translational models validate the findings by highlighting the potential avenues for therapeutic interventions.

DISCUSSION

The study’s strength lies in its broad approach, which encompasses a wide range of clinical data, including high-resolution molecular profiling, followed by experimental validation. The gap between observation and functional understanding is an essential step for translational impact, which has been bridged by combining human data with preclinical models.

The interpretation of abnormal IFNγ signaling and reduced antigen-presenting activity as key hallmarks of AR opens novel therapeutic perspectives. The anti-tumor immunity could be revolutionized with novel approaches that can restore interferon signaling, for example, by targeting downstream pathway components and merging agents that regulate IFN activity with checkpoint blockade^[2]. Similarly, reducing the deficiencies associated with antigen presentation is a considerable avenue. Techniques that increase the immunogenicity of the tumor via epigenetic modulators, personalized vaccines, and adoptive T cell therapies that detect neoantigens can tackle the tumor bypass mechanism. The combination of ICIs and agents targeting various pathways of immune evasion also needs considerable attention. Additionally, clinical observations of oligometastatic progression in patients with AR have noted that localized treatment can be incorporated into systemic therapy protocols. Recurrence can be slowed down, and progression-free survival can be enhanced by utilizing radiotherapy or excising resistant lesions.

The significance of real-time molecular monitoring has also been emphasized in this article. The early detection of resistance can be facilitated by producing efficient biomarkers that reflect the status and precise presentation of the interferon pathways, which may lead to effective therapeutic and clinical outcomes^[6].

From a clinical perspective, while the study sheds light on the molecular drivers of AR, its practical implications remain somewhat limited without clear, actionable guidelines. The identification of oligoprogression as a phenomenon of interest is crucial, yet the study does not provide definitive strategies on how best to integrate localized interventions such as radiation or resection into existing treatment regimens. Furthermore, the lack of predictive biomarkers for distinguishing patients likely to develop AR from those who will experience primary resistance remains a significant barrier to translating these findings into personalized treatment plans. For oncologists, the study leaves an unmet need for real-time monitoring tools capable of detecting early signs of AR before tumor progression becomes clinically evident. To make these molecular insights more clinically actionable, future studies must focus on developing biomarkers for early detection, as well as refining clinical trial designs to test combination therapies that address the evolving immune landscape of patients undergoing immune checkpoint blockade therapy.

The article “Clinical and molecular features of acquired resistance to immunotherapy in non-small cell lung cancer” provides insights into the remarkable advances in exploring the resistance mechanism towards immune checkpoint blockade. It provides a foundation for constructive, personalized therapeutic techniques by analyzing the clinical phenotypes and molecular changes responsible for acquiring resistance. Although handling the AR is a huge hurdle, with constant mechanical insights and innovative interventions, sustained immunotherapy can be achieved.

Nevertheless, a few limitations need to be considered. A relatively small subset of patients was considered for molecular analysis, which can restrain the representation of the outcomes given the resistance mechanism and heterogeneity of NSCLC. As a retrospective study, this work can identify associations but cannot establish direct cause and effect. Furthermore, the findings may be influenced by selection bias, as the patients who underwent biopsies may not be fully representative of the broader patient population. Furthermore, to explore long-term resistance dynamics and potential evolution, the timeframe of the analysis needs to be expanded. Additional investigations integrating large cohorts with recurrent biopsies along with multi-omics analysis may be crucial for the identification of early detection of biomarkers and temporal resistance complexity.

CONCLUSION

While this study presents a novel mechanism of AR to PD-L1 blockade in NSCLC, it remains to be explored whether this mechanism is specific to NSCLC or whether it applies to other cancer types. Future studies should investigate the broader applicability of this mechanism to better understand its role in resistance across multiple tumor types and refine immunotherapeutic approaches accordingly. It remains unclear whether the IFNγ-driven mechanism identified by Memon et al.^[1] (2024) acts independently or in conjunction with other known resistance pathways, such as Janus Kinase/Signal Transducer and Activator of Transcription (JAK/STAT) signaling alterations, Phosphatase and Tensin Homolog (PTEN) loss, T cell exhaustion, or upregulation of alternative immune checkpoints. The interaction of these pathways may have additive or synergistic effects, collectively shaping the resistant phenotype. Integrating this mechanism with the broader network of immune escape pathways will be critical to fully understand AR and design effective combinatorial therapies.