Understanding Acquired Resistance to Lung Cancer Immunotherapy
Explained in plain English
The fight against lung cancer has seen a powerful weapon emerge — immunotherapy using PD-(L)1 blockade.
This treatment has shown incredible success, providing hope to many patients with advanced non-small cell lung cancer (NSCLC). However, a significant challenge arises for more than half of the initial responders who develop acquired resistance (AR).
Despite its common occurrence, AR remains a mysterious and under-explored aspect of lung cancer treatment.
The Enigma of Acquired Resistance
Imagine a superhero fighting a formidable enemy. Initially, the superhero triumphs, but over time, the enemy adapts, and the superhero’s power becomes less effective. This is somewhat similar to what happens in the world of cancer treatment.
Even with the success of PD-(L)1 blockade, a large portion of patients faces acquired resistance, leading to disease progression.
The molecular secrets
To unravel the secrets of AR in lung cancer, researchers delved into a comprehensive study involving 1,201 patients with NSCLC treated with PD-1 blockade. Among these patients, a significant 20% initially responded to the treatment. However, a staggering 61% of these initial responders developed acquired resistance within five years.
Acquired resistance
In the superhero analogy, understanding how the enemy adapts is crucial. Similarly, scientists discovered that acquired resistance comes with changes in inflammation and interferon (IFN) signalling within the tumour cells. These alterations were identified by examining the expression of IFNγ response genes, revealing distinct patterns in relapsed tumours.
The IFNγ Response: Friend or Foe?
Interferon (IFN) signalling acts like a communication network within our body’s defence system. In the context of cancer treatment, changes in IFNγ response genes indicated potential routes of resistance. Some tumours showed an upregulation of these genes, suggesting a persistent IFN signalling, while others maintained stable expression.
This difference in IFNγ response played a crucial role in shaping the tumour’s behaviour.
From Humans to Mice: Validating Findings
To validate their discoveries, scientists turned to murine models, creating a parallel world where they could manipulate factors and observe outcomes. These mouse models, representing acquired resistance to PD-(L)1 blockade, mimicked the human experience.
Notably, in vitro treatment with IFNγ mirrored the altered IFN response seen in human tumours, providing a powerful tool for understanding resistance mechanisms.
The Battle Plan: Reprogramming Resistance
Armed with this knowledge, researchers now aim to devise strategies to overcome acquired resistance. The persistently inflamed tumour micro-environment, as opposed to an excluded or deserted one, emerged as a key factor. This finding is akin to mapping the battleground — a crucial aspect in planning a successful strategy.
By effectively reprogramming and reversing acquired resistance, scientists hope to enhance the effectiveness of immunotherapies in the future.In the battle against lung cancer, acquired resistance stands as a formidable adversary.
This research unveils the hidden aspects of this challenge, shedding light on the molecular intricacies at play, and as scientists struggle to unravel the language of tumours and immune responses, the hope is to refine existing treatments and pave the way for innovative strategies to conquer acquired resistance.
Hopefully this will bring us one step closer to a world where lung cancer is no longer an insurmountable foe.
Sources
Pembrolizumab plus Chemotherapy in Metastatic Non-Small-Cell Lung Cancer.
N. Engl. J. Med. 2018; 378: 2078–2092
